(4, 5, 6, 7-Tetrahydro-1-H-Indol-7-Yl) Acetic Acid Derivatives for Treatment of Alzheimer&#39;s Disease

ABSTRACT

Compounds of formula I:  
                 
are disclosed. The compounds are useful in treating or preventing diseases associated with deposition of Aβ in the brain.

This invention relates to methods and materials for use in therapeutictreatment of the human body. In particular, it provides materials fortreating diseases associated with the deposition of β-amyloid peptide inthe brain, such as Alzheimer's disease, or of preventing or delaying theonset of dementia associated with such diseases.

Alzheimer's disease (AD) is the most prevalent form of dementia. Itsdiagnosis is described in the Diagnostic and Statistical Manual ofMental Disorders, 4^(th) ed., published by the American PsychiatricAssociation (DSM-IV). It is a neurodegenerative disorder, clinicallycharacterized by progressive loss of memory and general cognitivefunction, and pathologically characterized by the deposition ofextracellular proteinaceous plaques in the cortical and associativebrain regions of sufferers. These plaques mainly comprise fibrillaraggregates of β-amyloid peptide (Aβ). Aβ is formed from amyloidprecursor protein (APP) via separate intracellular proteolytic eventsinvolving the enzymes β-secretase and γ-secretase. Variability in thesite of the proteolysis mediated by γ-secretase results in Aβ of varyingchain length, e.g. Aβ(1-38), Aβ(1-40) and Aβ(1-42). N-terminaltruncations such as Aβ(4-42) are also found in the brain, possibly as aresult of variability in the site of proteolysis mediated byβ-secretase. For the sake of convenience, expressions such as “Aβ(1-40)”and “Aβ(1-42)” as used herein are inclusive of such N-terminal truncatedvariants. After secretion into the extracellular medium, AD formsinitially-soluble aggregates which are widely believed to be the keyneurotoxic agents in AD (see Gong et al, PNAS, 100 (2003), 10417-22),and which ultimately result in the insoluble deposits and dense neuriticplaques which are the pathological characteristics of AD.

Other dementing conditions associated with deposition of Aβ in the braininclude cerebral amyloid angiopathy, hereditary cerebral haemorrhagewith amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementiapugilistica and Down syndrome.

Various interventions in the plaque-forming process have been proposedas therapeutic treatments for AD (see, for example, Hardy and Selkoe,Science, 297 (2002), 353-6). One such method of treatment that has beenproposed is that of blocking or attenuating the production of Aβ forexample by inhibition of β- or γ-secretase. It has also been reportedthat inhibition of glycogen synthase kinase-3 (GSK-3), in particularinhibition of GSK-3α, can block the production of Aβ (see Phiel et al,Nature, 423 (2003), 435-9).

Other proposed methods of treatment include administering a compoundwhich blocks the aggregation of Aβ, and administering an antibody whichselectively binds to Aβ.

An alternative method of treatment is that of modulation of the actionof γ-secretase so as to selectively attenuate the production ofAβ(1-42). This results in preferential secretion of the shorter chainisoforms of Aβ, which are believed to have a reduced propensity forself-aggregation and plaque formation, and hence are more easily clearedfrom the brain, and/or are less neurotoxic. Compounds showing thiseffect include certain non-steroidal antiinflammatory drugs (NSAIDs) andtheir analogues (see WO 01/8721 and US 2002/0128319 and Weggen et alNature, 414 (2001) 212-16; Morihara et al, J. Neurochem., 83 (2002),1009-12; and Takahashi et al, J. Biol. Chem., 278 (2003), 18644-70).Compounds which modulate the activity of PPARα and/or PPARδ are alsoreported to have the effect of lowering Aβ(1-42) (WO 02/100836). NSAIDderivatives capable of releasing nitric oxide have been reported to showimproved anti-neuroinflammatory effects and/or to reduce intracerebralAβ deposition in animal models (WO 02/092072; Jantzen et al, J.Neuroscience, 22 (2002), 226-54).

It has now been found that certain tetrahydroindole alkanoic acids andrelated compounds have the desirable property of selectively inhibitingproduction of Aβ(1-42).

According to the present invention there is provided a compound offormula I:

wherein V represents a bond, CH₂ or CH₂CH₂;

X represents CR^(1a) or N;

Y represents CO₂H or tetrazole;

Ar represents phenyl which optionally bears up to 3 substituentsindependently selected from hydrocarbon groups of up to 6 carbon atomsand (CH₂)_(m)-Z where m is 0, 1 or 2 and Z represents halogen, N₃, CN,CF₃, OCF₃, OR⁴, S(O)_(t)R⁴ where t is 0, 1 or 2, CO₂R⁴, tetrazole,N(R⁴)₂, NHCOR⁵, NHCON(R⁴)₂, CON(R⁴)₂, SO₂N(R⁴)₂, NHSO₂R⁵, COR⁵, orOCOR⁵;

R¹ represents H or a nonaromatic hydrocarbon group of up to 10 carbonatoms optionally substituted with up to 3 halogen substituents or withCN, CF₃, OR⁴, S(O)_(t)R⁴ where t is 0, 1 or 2, CO₂R⁴, CON(R⁴)₂,SO₂N(R⁴)₂, COR⁴, OCOR⁵ or NR⁴COR⁵;

or R¹ represents phenyl, naphthyl, benzyl or heteroaryl any of whichoptionally bears up to 3 substituents selected from halogen, CF₃, OCF₃,CN, NO₂R⁵, OR⁴, CO₂R⁴, S(O)_(t)R⁴ where t is 0, 1 or 2, CON(R⁴)₂,SO₂N(R⁴)₂, COR⁴, OCOR⁵ or NR⁴COR⁵;

R^(1a) has the same definition as R¹;

each R² is independently H or C₁₋₄alkyl;

R³ is H or a hydrocarbon group containing up to 10 carbon atoms which isoptionally substituted with halogen, CF₃, C₁₋₄alkoxy or C₁₋₄alkylthio;

R⁴ represents H or a hydrocarbon group of up to 7 carbon atoms,optionally substituted with halogen, CN, CF₃, OH, C₁₋₄alkoxy orC₁₋₄alkoxycarbonyl; or two R⁴ groups attached to the same nitrogen atommay complete a 5- or 6-membered heterocyclic ring;

R⁵ represents R⁴ that is other than H;

p is 0, 1 or 2; and

R⁶ represents C₁₋₆alkyl, C₂₋₆alkenyl or phenyl, benzyl or heteroaryl,said phenyl, benzyl or heteroaryl optionally bearing up to 3substituents selected from halogen, CN, CF₃, OCF₃, OR⁴, CO₂R⁴, COR⁴,OCOR⁵ and C₁₋₄alkyl;

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, R¹ represents H or a nonaromatic hydrocarbongroup of up to 10 carbon atoms optionally substituted with up to 3halogen substituents or with CN, CF₃, OR⁴, S(O)_(t)R⁴ where t is 0, 1 or2, CO₂R⁴, CON(R⁴)₂, SO₂N(R⁴)₂, COR⁴, OCOR⁵ or NR⁴COR⁵;

or R¹ represents phenyl, benzyl or heteroaryl any of which optionallybears up to 3 substituents selected from halogen, CF₃, OCF₃, CN, R⁵,OR⁴, CO₂R⁴, S(O)_(t)R⁴ where t is 0, 1 or 2, CON(R⁴)₂, SO₂N(R⁴)₂, COR⁴,OCOR⁵ or NR⁴COR⁵;

R^(1a) has the same definition as R¹ with the proviso that when X isCR^(1a), at least one of R¹ and R^(1a) is H or C₁₋₄ alkyl; and all othervariables are as defined above.

Where a variable occurs more than once in formula I or in a substituentthereof, the individual occurrences of that variable are independent ofeach other, unless otherwise specified.

As used herein, the expression “hydrocarbon group” refers to groupsconsisting solely of carbon and hydrogen atoms. Such groups may compriselinear, branched or cyclic structures, singly or in any combinationconsistent with the indicated maximum number of carbon atoms, and may besaturated or unsaturated, including aromatic when the indicated maximumnumber of carbon atoms so permits unless otherwise indicated.

As used herein, the expression “C_(1-x)alkyl” where x is an integergreater than 1 refers to straight-chained and branched alkyl groupswherein the number of constituent carbon atoms is in the range 1 to x.Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl andt-butyl. Derived expressions such as “C₂₋₆alkenyl”, “hydroxyC₁₋₆alkyl”,“heteroarylC₁₋₆alkyl”, “C₂₋₆alkynyl” and “C₁₋₆alkoxy” are to beconstrued in an analogous manner. Most suitably, the number of carbonatoms in such groups is not more than 6.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, of which fluorine and chlorine are preferred.

The term “heteroaryl” as used herein means a cyclic or polycyclic systemof up to 10 ring atoms selected from C, N, O and S, wherein at least oneof the constituent rings is aromatic and wherein at least one atom ofthe aromatic ring is other than carbon. Preferably not more than 3 ringatoms are other than carbon. Examples of heteroaryl groups includepyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl,thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, oxadiazolyl, triazolyl and thiadiazolyl groups andbenzo-fused analogues thereof. Further examples of suitable heteroarylring systems include 1,2,4-triazine, 1,3,5-triazine,1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline.Monocyclic 5- or 6-membered systems are preferred, especially pyridineor thiophene.

For use in medicine, the compounds of formula I may be in the form ofpharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds of formula I or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid,methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid,succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid,tartaric acid, carbonic acid or phosphoric acid. Alternatively, wherethe compound of the invention carries an acidic moiety, apharmaceutically acceptable salt may be formed by neutralisation of saidacidic moiety with a suitable base. Examples of pharmaceuticallyacceptable salts thus formed include alkali metal salts such as sodiumor potassium salts; ammonium salts; alkaline earth metal salts such ascalcium or magnesium salts; and salts formed with suitable organicbases, such as amine salts (including pyridinium salts) and quaternaryammonium salts.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

In formula I, V represents a bond, CH₂ or CH₂CH₂. In a preferredembodiment V represents CH₂.

X represents N or CR^(1a), preferably CR^(1a).

R³ represents H or a hydrocarbon group of up to 10 carbon atoms which isoptionally substituted as defined previously. Suitable identities for R³include H; alkyl (especially C₁₋₆alkyl such as methyl, ethyl, n-propyl,isopropyl, 2-methylpropyl, n-butyl, 3-methylbutyl and3,3-dimethylbutyl); substituted alkyl (such as methoxymethyl,methylthiomethyl and 3,3,3-trifluoropropyl); cycloalkyl (especiallyC₃₋₆cycloalkyl such as cyclopropyl, cyclopentyl and cyclohexyl);cycloalkylalkyl (such as cyclopropylmethyl); aryl (such as phenyl and4-trifluoromethylphenyl) and arylalkyl (such as benzyl and phenethyl).In a particular embodiment, R³ is an optionally-substituted hydrocarbongroup of 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, and inparticular an alkyl group of 2 to 6 carbon atoms. In a preferredembodiment, R³ is n-propyl, n-butyl or 3-methylbutyl.

Y represents CO₂H or tetrazole (in particular 1,2,3,4-tetrazol-5-yl),but preferably represents CO₂H.

Ar represents phenyl which is optionally substituted as definedpreviously. Phenyl groups represented by Ar optionally bear up to 3substituents as defined previously. When said substituents comprise agroup represented by (CH₂)_(m)-Z, m is preferably 0 or 1, mostpreferably 0. When Ar represents mono-substituted phenyl, thesubstituent aptly occupies the 4-position. Examples of suitablesubstituents include halogen (especially Cl and F), N₃, CF₃, OCF₃, OH,OMe, SMe, NHCOMe, SO₂Me, CO₂H, CO₂Me, C₁₋₄alkyl (such as methyl, ethyl,n-propyl and isopropyl), CON(Me)₂, COMe, SO₂N(Me)₂, NHSO₂Me andNHCONHMe. Preferred substituents include Cl, F, N₃, OCF₃, CF₃ and OMe.

Specific examples of groups represented by Ar include phenyl,4-chlorophenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-azidophenyl,4-methoxyphenyl, 4-trifluoromethoxyphenyl,2,4-bis(trifluoromethyl)phenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,2,4,6-trifluorophenyl and 4-iodophenyl, of which 4-trifluoromethylphenylis particularly preferred.

R¹ preferably represents H or a hydrocarbon group of up to 6 carbonatoms, or phenyl, naphthyl, benzyl or heteroaryl, any of which may besubstituted as defined previously. Very suitably, R¹ representsoptionally-substituted phenyl or heteroaryl (such as thiophene).Preferred substituents include halogen (especially Cl, Br or F), C₁₋₆alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and2-methylpropyl), OCF₃, methoxy and CF₃. Specific examples of groupsrepresented by R¹ include H, phenyl, 4-methylphenyl, 4-isopropylphenyl,2-chlorophenyl, 2-bromophenyl, 2-trifluoromethylphenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,4-chlorophenyl, 3-trifluoromethylphenyl, 2-bromo-4-chlorophenyl,2-n-butyl-4-chlorophenyl, 4-chloro-2-(2-methylpropyl)phenyl and5-chloro-2-thienyl.

Further specific examples of groups represented by R¹ include4-chloro-2-methylphenyl, 2,4-dimethylphenyl, 4-cyanophenyl,2,4-bis(trifluoromethyl)phenyl, 4-trifluoromethylphenyl,2,4-dimethoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl,4-methyl-1-naphthyl, 2-nitrophenyl, 4-trifluoromethoxyphenyl,5-chlorobiphenyl-2-yl, 2,4,6-trichlorophenyl,2,5-bis(trifluoromethyl)phenyl, 2,4-difluorophenyl,4-chloro-2-fluorophenyl and t-butyl.

R^(1a) has the same definition as R¹, i.e. is selected from the samerange of chemical structures, but is preferably not identical to R¹.Preferred identities for R^(1a) include H, C₁₋₆alkyl (such as methyl,ethyl, isopropyl and t-butyl), C₃₋₇cycloalkyl (such as cyclohexyl) andphenyl which is optionally-substituted as described for R¹ (inparticular 4-trifluoromethylphenyl and 2,4-dichlorophenyl). In oneembodiment, when X is CR^(1a) at least one of R¹ and R^(1a) is H or C₁₋₄alkyl. In another embodiment, R¹ represents optionally-substitutedphenyl, naphthyl or heteroaryl and R^(1a) represents H, C₁₋₆alkyl orC₃₋₇cycloalkyl, preferably H or C₁₋₄alkyl.

In a further embodiment, R¹ represents H and R^(1a) representsC₁₋₆alkyl, C₃₋₇cycloalkyl or optionally-substituted phenyl.

Each R² is independently H or C₁₋₄alkyl such as methyl or ethyl.Preferably one R² is H and the other is H or methyl. Most preferably,both R² groups are H.

When present, R⁶ represents linear or branched C₁₋₆alkyl (preferablyC₁₋₄alkyl) such as methyl, ethyl, n-propyl, isopropyl or t-butyl, C₂₋₆alkenyl such as vinyl or allyl, or phenyl, heteroaryl or benzyl which isoptionally substituted as defined previously. Preferred substituentsinclude halogen (especially Cl or F), OCH₃, OCF₃, CF₃ and C₁₋₄alkyl(such as methyl). A preferred heteroaryl group is pyridyl, especially3-pyridyl. Examples of groups represented by R⁶ include methyl, ethyl,isopropyl, vinyl, 3-pyridyl, phenyl, 4-chlorophenyl, 3-fluorophenyl,4-fluorophenyl, 4-fluoro-3-methylphenyl, 4-methoxyphenyl,3,4-dichlorophenyl, 3,4-difluorophenyl and 2,5-dimethylphenyl. Preferredexamples include 4-fluorophenyl. An R⁶ group may be attached at anyavailable position of the ring, including the carbon atom bearing the—C(R²)₂—Y moiety and any carbon atom included in V. Where two R⁶ groupsare present, they may be the same or different and may be attached tothe same or different ring positions. When p is 2, preferably not morethan one of the R⁶ groups is optionally-substituted phenyl, heteroarylor benzyl.

A subset of the compounds of Formula I is defined by Formula II:

wherein V, Ar, p, R¹, R^(1a), R², R³ and R⁶ have the same definitionsand preferred identities as before.

A subset of the compounds in accordance with formula II comprises the1-arylalkyl-4,5,6,7-tetrahydroindol-7-yl acetic acid derivatives inwhich V is CH₂ and each R² is H. Within this embodiment, p is preferably0 or p is 1 and R⁶ is attached in the 4-position or the 6-position. Aris very suitably 4-trifluoromethylphenyl, R¹ is very suitably selectedfrom the examples listed earlier herein, R^(1a) is very suitablyselected from H or C₁₋₄alkyl, and R³ is very suitably n-propyl, n-butylor 3-methylbutyl.

A second subset of the compounds of formula I is defined by formula III:

wherein V, Ar, p, R^(1a), R², R³ and R⁶ have the same definitions andpreferred identities as before. Preferred compound within this subsetinclude those in which V represents CH₂ and either p is 0 or p is 1 andR⁶ represents an alkyl substituent in the 6-position, especially ethyl.In formula III, Ar preferably represents 4-trifluoromethylphenyl, eachR² is preferably H, R³ is preferably n-propyl, n-butyl or 3-methylbutyl,and R^(1a) is preferably selected from C₁₋₆alkyl (especially methyl,ethyl, isopropyl or t-butyl), C₃₋₇ cycloalkyl (especially cyclohexyl),or optionally-substituted phenyl (especially 4-trifluoromethylphenyl or2,4-dichlorophenyl).

A third subset of the compounds of formula I is defined by formula IV:

where V, p, Ar, R¹, R², R³ and R⁶ have the same definitions andpreferred identities as before.

Specific examples of compounds in accordance with formula I are providedin the Examples appended hereto.

Compounds of formula I in which X represents CH may be obtained byreaction of an imine (1) with a nitro-olefin (2):

wherein V, Ar, Y, p, R², R³, R⁶ and R¹ have the same meanings as before.Preferably R¹ is optionally substituted phenyl or heteroaryl. Thereaction takes place in toluene solution, eg at reflux or by heating ina microwave apparatus.

Imines of formula (1) are conveniently generated in situ by reaction ofan amine (3) with a cyclohexanone of formula (4):

where V, Ar, R³, Y, p, R² and R⁶ have the same meanings as before. Thereaction can be carried out in toluene with azeotropic removal of water.

Amines (3) may be obtained by treating ketones Ar—CO—R³ withhydroxylamine and hydrogenating the resulting oximes over Raney nickel.Alternatively, ketones Ar—CO—R³ may be condensed withα-methylbenzylamine and the resulting imines reduced (using NaBH₄) toprovide bis(benzylamines) ArCH(R³)—NH—CH(CH₃)Ph, from which the desiredamines (3) are obtained by hydrogenation over Pd/C. Use of a chiralα-methylbenzylamine facilitates isolation of amines (3) as singleenantiomers, enabling control of the stereochemistry at one of thechiral centres in formula I.

Compounds of formula I in which X represents CR^(1a) may be obtained byreaction of an amine (3) with a 1,4-dicarbonyl compound (5):

The reaction takes place in toluene solution in the presence of an acidcatalyst (eg. acetic acid) with azeotropic removal of water.Alternatively, the reaction can be carried out in dichloromethane at−78° C. in the presence of triethylamine and TiCl₄.

Compounds (5) are available by reaction of an enamine (6):

with a halo-ketone R^(1a)—CO—CH(R¹)-Hal where Hal is chloride orbromide. The reaction takes place in DMF at ambient temperature and isparticularly suitable when R¹ is H or alkyl.

Enamines (6) are formed from ketones (4) by refluxing with pyrrolidinein toluene solution using an acid catalyst such as acetic acid withazeotropic removal of water.

A preferred route to dicarbonyl compounds (5) comprises oxidativecleavage of olefins (7):

where V, Y, p, R¹, R^(1a), R² and R⁶ have the same meanings as before.The cleavage may be effected by ozonolysis in methanol/dichloromethane,or alternatively by treatment with RuCl₃ and NaIO₄. Ozonolysis ispreferred when R^(1a) is H.

Olefins (7) may be obtained by treatment of ketones (4) withtriethylorthoformate, and reaction of the resulting diethyl ketals withan allylic alcohol (8):

where R¹ and R^(1a) have the same meanings as before. The reaction maybe carried out at about 125° C. in the presence of propionic acid. Theinitial product is an enol ether which undergoes Claisen rearrangementto provide the olefin (7).

In an alternative route to compounds of formula I in which X representsC—CH₃ and R¹ is H, alkynes (9):

may be substituted for diketones (5). Alkynes (9) are formed by reactionof enamines (6) with propargyl bromide in toluene at 80° C.

Compounds of formula I in which X is N may be obtained by reaction ofdiketones (10) with hydrazines (11):

The reaction takes place in refluxing ethanol. Diketones (10) areavailable by reaction of enamines (6) with R¹—COCl. Hydrazines (11) areavailable by reaction of Ar—CH(R³)—Br with hydrazine hydrate inisopropanol at 70° C. (see also EP 0234708).

During all of the chemical processes described above, a carboxylic acidgroup represented by Y is preferably protected as the methyl ester orethyl ester, the free acid being regenerated by hydrolysis in a finalstep, e.g. using LiOH in aqueous THF or dioxan.

Where they are not commercially available, the starting materials usedin the schemes outlined above may be obtained by published routes orsimple adaptations thereof. Suitable methods are described in theExamples section herein.

Since the compounds of Formula I have at least one asymmetric centre,they accordingly exist in enantiomeric forms. If desired, the individualenantiomers may be isolated in pure form by conventional means. Forexample, a racemic mixture may be resolved into its componentenantiomers by preparative chiral HPLC, or by treatment with anoptically pure amine to form diastereomeric salt pairs, separable byfractional crystallisation, from which the optically pure acids may beregenerated. Similarly, a racemic acid may be reacted with an opticallypure alcohol or amine to form pairs of diastereomeric esters or amideswhich may be separated by chromatography or fractional crystallisationand hydrolysed to yield enantiomerically-pure acids. These resolutiontechniques may equally well be practised on the synthetic precursors ofthe compounds of Formula I, and the resulting optically-pureintermediates used to prepare compounds of Formula I in optically-pureform.

The invention further provides a pharmaceutical composition comprisingcompound of formula I or pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

Preferably these compositions are in unit dosage forms such as tablets,pills, capsules, powders, granules, sterile parenteral solutions orsuspensions, metered aerosol or liquid sprays, drops, ampoules,transdermal patches, auto-injector devices or suppositories; for oral,parenteral, intranasal, sublingual or rectal administration, or foradministration by inhalation or insufflation. The principal activeingredient typically is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalciumphosphate, or gums, dispersing agents, suspending agents or surfactantssuch as sorbitan monooleate and polyethylene glycol, and otherpharmaceutical diluents, e.g. water, to form a homogeneouspreformulation composition containing a compound of the presentinvention, or a pharmaceutically acceptable salt thereof. When referringto these preformulation compositions as homogeneous, it is meant thatthe active ingredient is dispersed evenly throughout the composition sothat the composition may be readily subdivided into equally effectiveunit dosage forms such as tablets, pills and capsules. Thispreformulation composition is then subdivided into unit dosage forms ofthe type described above containing from 0.1 to about 500 mg of theactive ingredient of the present invention. Typical unit dosage formscontain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, ofthe active ingredient. Tablets or pills of the composition can be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For example, the tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with such materials asshellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the compositions useful in the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, liquid- or gel-filled capsules, suitablyflavoured syrups, aqueous or oil suspensions, and flavoured emulsionswith edible oils such as cottonseed oil, sesame oil, coconut oil orpeanut oil, as well as elixirs and similar pharmaceutical vehicles.Suitable dispersing or suspending agents for aqueous suspensions includesynthetic and natural gums such as tragacanth, acacia, alginate,dextran, sodium carboxymethylcellulose, methylcellulose, poly(ethyleneglycol), poly(vinylpyrrolidone) or gelatin.

The invention also provides a compound of formula I or apharmaceutically acceptable salt thereof for use in therapy, inparticular for use in treatment or prevention of a disease associatedwith deposition of Aβ in the brain.

The invention further provides the use of a compound of formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for treatment or prevention of a disease associated withdeposition of Aβin the brain.

The disease associated with deposition of Aβ in the brain is typicallyAlzheimer's disease (AD), cerebral amyloid angiopathy, multi-infarctdementia, dementia pugilistica or Down syndrome, preferably AD.

In another aspect, the invention provides the use of a compound ofFormula I as defined above, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for treating, preventing ordelaying the onset of dementia associated with Alzheimer's disease,cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementiapugilistica or Down syndrome.

The invention also provides a method of treating or preventing a diseaseassociated with deposition of Aβ in the brain comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of Formula I as defined above or a pharmaceutically acceptablesalt thereof.

In a further aspect, the invention provides a method of treating,preventing or delaying the onset of dementia associated with Alzheimer'sdisease, cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia,dementia pugilistica or Down syndrome comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula I as defined above or a pharmaceutically acceptable saltthereof.

The compounds of Formula I modulate the action of γ-secretase so as toselectively attenuate production of the (1-42) isoform of Aβ withoutsignificantly lowering production of the shorter chain isoforms such asAβ(1-40). This results in secretion of Aβ which has less tendency toself-aggregate and form insoluble deposits, is more easily cleared fromthe brain, and/or is less neurotoxic. Therefore, a further aspect of theinvention provides a method for retarding, arresting or preventing theaccumulation of Aβ in the brain comprising administering to a subject inneed thereof a therapeutically effective amount of a compound of FormulaI as defined above or a pharmaceutically acceptable salt thereof.

Because the compounds of formula I modulate the activity of γ-secretase,as opposed to suppressing said activity, it is believed that thetherapeutic benefits described above will be obtained with a reducedrisk of side effects, e.g. those that might arise from a disruption ofother signalling pathways (e.g. Notch) which are also controlled byγ-secretase.

In one embodiment of the invention, the compound of Formula I isadministered to a patient suffering from AD, cerebral amyloidangiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistica orDown syndrome, preferably AD.

In an alternative embodiment of the invention, the compound of Formula Iis administered to a patient suffering from mild cognitive impairment orage-related cognitive decline. A favourable outcome of such treatment isprevention or delay of the onset of AD. Age-related cognitive declineand mild cognitive impairment (MCI) are conditions in which a memorydeficit is present, but other diagnostic criteria for dementia areabsent (Santacruz and Swagerty, American Family Physician, 63 (2001),703-13). (See also “The ICD-10 Classification of Mental and BehaviouralDisorders”, Geneva: World Health Organisation, 1992, 64-5). As usedherein, “age-related cognitive decline” implies a decline of at leastsix months' duration in at least one of: memory and learning; attentionand concentration; thinking; language; and visuospatial functioning anda score of more than one standard deviation below the norm onstandardized neuropsychologic testing such as the MMSE. In particular,there may be a progressive decline in memory. In the more severecondition MCI, the degree of memory impairment is outside the rangeconsidered normal for the age of the patient but AD is not present. Thedifferential diagnosis of MCI and mild AD is described by Petersen etal., Arch. Neurol., 56 (1999), 303-8. Further information on thedifferential diagnosis of MCI is provided by Knopman et al, Mayo ClinicProceedings, 78 (2003), 1290-1308. In a study of elderly subjects,Tuokko et al (Arch, Neurol., 60 (2003) 577-82) found that thoseexhibiting MCI at the outset had a three-fold increased risk ofdeveloping dementia within 5 years.

Grundman et al (J. Mol. Neurosci., 19 (2002), 23-28) report that lowerbaseline hippocampal volume in MCI patients is a prognostic indicatorfor subsequent AD. Similarly, Andreasen et al (Acta Neurol. Scand, 107(2003) 47-51) report that high CSF levels of total tau, high CSF levelsof phospho-tau and lowered CSF levels of Aβ42 are all associated withincreased risk of progression from MCI to AD.

Within this embodiment, the compound of Formula I is advantageouslyadministered to patients who suffer impaired memory function but do notexhibit symptoms of dementia. Such impairment of memory functiontypically is not attributable to systemic or cerebral disease, such asstroke or metabolic disorders caused by pituitary dysfunction. Suchpatients may be in particular people aged 55 or over, especially peopleaged 60 or over, and preferably people aged 65 or over. Such patientsmay have normal patterns and levels of growth hormone secretion fortheir age. However, such patients may possess one or more additionalrisk factors for developing Alzheimer's disease. Such factors include afamily history of the disease; a genetic predisposition to the disease;elevated serum cholesterol; and adult-onset diabetes mellitus.

In a particular embodiment of the invention, the compound of Formula Iis administered to a patient suffering from age-related cognitivedecline or MCI who additionally possesses one or more risk factors fordeveloping AD selected from: a family history of the disease; a geneticpredisposition to the disease; elevated serum cholesterol; adult-onsetdiabetes mellitus; elevated baseline hippocampal volume; elevated CSFlevels of total tau; elevated CSF levels of phospho-tau; and lowered CSFlevels of Aβ(1-42).

A genetic predisposition (especially towards early onset AD) can arisefrom point mutations in one or more of a number of genes, including theAPP, presenilin-1 and presenilin-2 genes. Also, subjects who arehomozygous for the ε4 isoform of the apolipoprotein E gene are atgreater risk of developing AD.

The patient's degree of cognitive decline or impairment isadvantageously assessed at regular intervals before, during and/or aftera course of treatment in accordance with the invention, so that changestherein may be detected, e.g. the slowing or halting of cognitivedecline. A variety of neuropsychological tests are known in the art forthis purpose, such as the Mini-Mental State Examination (MMSE) withnorms adjusted for age and education (Folstein et al., J. Psych. Res.,12 (1975), 196-198, Anthony et al., Psychological Med., 12 (1982),397-408; Cockrell et al., Psychopharmacology, 24 (1988), 689-692; Crumet al., J. Am. Med. Assoc'n. 18 (1993), 2386-2391). The MMSE is a brief,quantitative measure of cognitive status in adults. It can be used toscreen for cognitive decline or impairment, to estimate the severity ofcognitive decline or impairment at a given point in time, to follow thecourse of cognitive changes in an individual over time, and to documentan individual's response to treatment. Another suitable test is theAlzheimer Disease Assessment Scale (ADAS), in particular the cognitiveelement thereof (ADAS-cog) (See Rosen et al., Am. J. Psychiatry, 141(1984), 1356-64).

For treating or preventing Alzheimer's disease, a suitable dosage levelis about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kgper day, and more preferably about 0.05 to 50 mg/kg of body weight perday, of the active compound.

The compounds may be administered on a regimen of 1 to 4 times per day.In some cases, however, a dosage outside these limits may be used.

The compounds of Formula I optionally may be administered in combinationwith one or more additional compounds known to be useful in thetreatment or prevention of AD or the symptoms thereof. Such additionalcompounds thus include cognition-enhancing drugs such asacetylcholinesterase inhibitors (e.g. donepezil and galanthamine), NMDAantagonists (e.g. memantine) or PDE4 inhibitors (e.g. Ariflo™ and theclasses of compounds disclosed in WO 03/018579, WO 01/46151, WO02/074726 and WO 02/098878). Such additional compounds also includecholesterol-lowering drugs such as the statins, e.g. simvastatin. Suchadditional compounds similarly include compounds known to modify theproduction or processing of Aβ in the brain (“amyloid modifiers”), suchas compounds which inhibit the secretion of Aβ (including γ-secretaseinhibitors, β-secretase inhibitors, and GSK-3α inhibitors), compoundswhich inhibit the aggregation of Aβ, and antibodies which selectivelybind to Aβ.

In this embodiment of the invention, the amyloid modifier may be acompound which inhibits the secretion of Aβ, for example an inhibitor ofγ-secretase (such as those disclosed in WO 01/53255, WO 01/66564, WO01/70677, WO 01/90084, WO 01/77144, WO 02/30912, WO 02/36555, WO02/081435, WO 02/081433, WO 03/018543, WO 03/013506, WO 03/013527 and WO03/014075), or a β-secretase inhibitor (such as those disclosed in WO03/037325, WO 03/030886, WO 03/006013, WO 03/006021, WO 03/006423, WO03/006453, WO 02/002122, WO 01/70672, WO 02/02505, WO 02/02506, WO02/02512, WO 02/02520, WO 02/098849 and WO 02/100820), or any othercompound which inhibits the formation or release of Aβ including thosedisclosed in WO 98/28268, WO 02/47671, WO 99/67221, WO 01/34639, WO01/34571, WO 00/07995, WO 00/38618, WO 01/92235, WO 01/77086, WO01/74784, WO 01/74796, WO 01/74783, WO 01/60826, WO 01/19797, WO01/27108, WO 01/27091, WO 00/50391, WO 02/057252, US 2002/0025955 andUS2002/0022621, and also including GSK-3 inhibitors, particularly GSK-3αinhibitors, such as lithium, as disclosed in Phiel et al, Nature, 423(2003), 435-9.

Within this embodiment, the amyloid modifier is advantageously aγ-secretase inhibitor, preferred examples of which include a compound offormula XI:

wherein:

m is 0 or 1;

Z represents halogen, CN, NO₂, N₃, CF₃, OR^(2a), N(R^(2a))₂, CO₂R^(2a),OCOR^(2a), COR^(2a), CON(R^(2a))₂, OCON(R^(2a))₂, CONR^(2a)(OR^(2a)),CON(R^(2a))N(R^(2a))₂)

CONHC(═NOH)R^(2a), heterocyclyl, phenyl or heteroaryl, saidheterocyclyl, phenyl or heteroaryl bearing 0-3 substituents selectedfrom halogen, CN, NO₂, CF₃, OR^(2a), N(R^(2a))₂, CO₂R^(2a), COR^(2a),CON(R^(2a))₂ and C₁₋₄alkyl;

R^(1b) represents H, C₁₋₄alkyl or OH;

R^(1c) represents H or C₁₋₄alkyl;

with the proviso that when m is 1, R^(1b) and R^(1c) do not bothrepresent C₁₋₄alkyl;

Ar¹ represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;

Ar² represents C₆₋₁₀aryl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, OH,OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;

R^(2a) represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, any of which optionally bears a substituent selected fromhalogen, CN, NO₂, CF₃, OR^(2b), CO₂R^(2b), N(R^(2b))₂, CON(R^(2b))₂, Arand COAr; or R^(2a) represents Ar; or two R^(2a) groups together with anitrogen atom to which they are mutually attached may complete anN-heterocyclyl group bearing 0-4 substituents independently selectedfrom ═O, ═S, halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, CO₂H, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,carbamoyl, Ar and COAr;

R^(2b) represents H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₆alkyl,C₂₋₆alkenyl, any of which optionally bears a substituent selected fromhalogen, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr; or R^(2b)represents Ar; or two R^(2b) groups together with a nitrogen atom towhich they are mutually attached may complete an N-heterocyclyl groupbearing 0-4 substituents independently selected from ═O, ═S, halogen,C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, CO₂H,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, carbamoyl, Ar and COAr;

Ar represents phenyl or heteroaryl bearing 0-3 substituents selectedfrom halogen, C₁₋₄alkyl, CN, NO₂, CF₃, OH, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,carbamoyl, C₁₋₄alkylcarbamoyl and di(C₁₋₄alkyl)carbamoyl;

“heterocyclyl” at every occurrence thereof means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein noneof the constituent rings is aromatic and wherein at least one ring atomis other than C; and

“heteroaryl” at every occurrence thereof means a cyclic or polycyclicsystem of up to 10 ring atoms selected from C, N, O and S, wherein atleast one of the constituent rings is aromatic and wherein at least onering atom of said aromatic ring is other than C;

or a pharmaceutically acceptable salt thereof.

Such compounds may be prepared as described in WO 03/018543. Preferredexamples include those defined by formula XIa:

and the pharmaceutically acceptable salts thereof, wherein m is 0 or 1,X is Cl or CF₃, and Y is OH, OC₁₋₆alkyl, NH₂ or NHC₁₋₆alkyl. Particularexamples include those in which m is 1 and Y is OH (or the sodium saltsthereof), and those in which m is 0 and Y is NH₂ or NHC₁₋₆alkyl.

Another preferred class of γ-secretase inhibitors for use in thisembodiment of the invention is that defined by formula XII:

wherein X is a bivalent pyrazole, imidazole, triazole, oxazole,isoxazole, thiazole, isothiazole, thiadiazole or 1,3,4-oxadiazoleresidue optionally bearing a hydrocarbon substituent comprising 1-5carbon atoms which is optionally substituted with up to 3 halogen atoms;andR is selected from:

(i) CP₃ or a non-aromatic hydrocarbon group of up to 10 carbon atoms,optionally substituted with halogen, CF₃, CHF₂, CN, OH, CO₂H, C₂₋₆acyl,C₁₋₄alkoxy or C₁₋₄alkoxycarbonyl;

(ii) a non-aromatic heterocyclic group comprising up to 7 ring atoms ofwhich up to 3 are chosen from N, O and S and the remainder are carbon,bearing 0-3 substituents independently selected from oxo, halogen, CN,C₁₋₆alkyl, OH, CF₃, CHF₂, CH₂F, C₂₋₆acyl, CO₂H, C₁₋₄alkoxy andC₁₋₄alkoxycarbonyl;

(iii) phenyl or 6-membered heteroaryl, either of which bears 0-3substituents independently selected from halogen, CF₃, CHF₂, CH₂F, NO₂,CN, OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy; and

(iv) N(R^(a))₂ where each R^(a) independently represents H or C₁₋₆alkylwhich is optionally substituted with halogen, CF₃, CHF₂, CN, OH, CO₂H,C₂₋₆acyl, C₁₋₄alkoxy or C₁₋₄alkoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

X is very aptly 5-substituted-thiazol-2-yl,5-substituted-4-methylthiazol-2-yl, 5-substituted-1-methylpyrazol-3-yl,1-substituted-imidazol-4-yl or 1-substituted-1,2,4-triazol-3-yl.Preferably, R represents optionally-substituted phenyl or heteroarylsuch as phenyl, monohalophenyl, dihalophenyl, trihalophenyl,cyanophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl,trifluoromethoxyphenyl, pyridyl, monohalopyridyl andtrifluoromethylpyridyl, wherein “halo” refers to fluoro or chloro.Particularly preferred identities of R—X— include5-(4-fluorophenyl)-1-methylpyrazol-3-yl,5-(4-chlorophenyl)-1-methylpyrazol-3-yl and1-(4-fluorophenyl)imidazol-4-yl. Such compounds may be prepared bymethods disclosed in WO 03/093252.

Alternatively, the amyloid modifier may be a compound which inhibits theaggregation of Aβ. Suitable examples include chelating agents such asclioquinol (Gouras and Beal, Neuron, 30 (2001), 641-2) and the compoundsdisclosed in WO 99/16741, in particular that known as DP-109 (Kalendarevet al, J. Pharm. Biomed. Anal., 24 (2001), 967-75). Other inhibitors ofAD aggregation suitable for use in the invention include the compoundsdisclosed in WO 96/28471, WO 98/08868 and WO 00/052048, including thecompound known as Apan™ (Praecis); WO 00/064420, WO 03/017994, WO99/59571 and the compound known as Alzhemed™ (Neurochem); WO 00/149281and the compositions known as PTI-777 and PTI-00703 (ProteoTech); WO96/39834, WO 01/83425, WO 01/55093, WO 00/76988, WO 00/76987, WO00/76969, WO 00/76489, WO 97/26919, WO 97/16194, and WO 97/16191.

Alternatively, the amyloid modifier may be an antibody which bindsselectively to Aβ. Said antibody may be polyclonal or monoclonal, but ispreferably monoclonal, and is preferably human or humanized. Preferably,the antibody is capable of sequestering soluble Aβ from biologicalfluids, as described in WO 03/016466, WO 03/016467, WO 03/015691 and WO01/62801. Suitable antibodies include humanized antibody 266 (describedin WO 01/62801) and the modified version thereof described in WO03/016466. Suitable antibodies also include those specific to Aβ-deriveddiffusible ligands (ADDLS), as disclosed in WO 2004/031400.

As used herein, the expression “in combination with” requires thattherapeutically effective amounts of both the compound of Formula I andthe additional compound are administered to the subject, but places norestriction on the manner in which this is achieved. Thus, the twospecies may be combined in a single dosage form for simultaneousadministration to the subject, or may be provided in separate dosageforms for simultaneous or sequential administration to the subject.Sequential administration may be close in time or remote in time, e.g.one species administered in the morning and the other in the evening.The separate species may be administered at the same frequency or atdifferent frequencies, e.g. one species once a day and the other two ormore times a day. The separate species may be administered by the sameroute or by different routes, e.g. one species orally and the otherparenterally, although oral administration of both species is preferred,where possible. When the additional compound is an antibody, it willtypically be administered parenterally and separately from the compoundof Formula I.

In a further aspect, the invention provides the combination of acompound of formula I or a pharmaceutically acceptable salt thereof anda compound of formula XI(a) or a pharmaceutically acceptable saltthereof for use in treatment or prevention of a disease associated withdeposition of β-amyloid in the brain. Said use may involve thesimultaneous or separate administration of the respective compounds to apatient in need of such treatment or prevention.

In a further aspect, the invention provides a pharmaceutical compositioncomprising, in a pharmaceutically acceptable carrier, a compound offormula I or a pharmaceutically acceptable salt thereof and a compoundof formula XI(a) or a pharmaceutically acceptable salt thereof.Preferably, the pharmaceutical composition is in a unit dose formsuitable for oral administration, such as a tablet or a capsule.

The ability of the compounds of Formula I to selectively inhibitproduction of Aβ(1-42) was determined using the following assay:

Cell-Based γ-Secretase Assay

Human SH-SY5Y neuroblastoma cells overexpressing the direct γ-secretasesubstrate SPA4CT were induced with sodium butyrate (10 mM) for 4 hoursprior to plating. Cells were plated at 35,000 cells/well/100 μl in96-well plates in phenol red-free MEM/10% FBS, 50 mM HEPES, 1% Glutamineand incubated for 2 hrs at 37° C., 5% CO₂.

Compounds for testing were diluted into Me₂SO to give a ten pointdose-response curve. Typically 10 μl of these diluted compounds in Me₂SOwere further diluted into 182 μl dilution buffer (phenol red-freeMEM/10% FBS, 50 mM HEPES, 1% Glutamine) and 10 μl of each dilution wasadded to the cells in 96-well plates (yielding a final Me₂SOconcentration of 0.5%). Appropriate vehicle and inhibitor controls wereused to determine the window of the assay.

After incubation overnight at 37° C., 5% CO₂, 10 μl and 50 μl media weretransferred into a fresh Costar round-bottom 96-well plate for detectionof Aβ(40) and Aβ(42) peptides, respectively. 40 μl Origen buffer (PBS,2% BSA, 0.2% Tween-20) was added to the Aβ(40) wells followed by theaddition of 25 μl the respective antibody premixes to the wells:

Aβ(40) premix: 1 μg/ml ruthenylated G2-10 antibody, 4 μg/ml

biotinylated 4G8 antibody diluted in Origen buffer

Aβ(42) premix: 0.5 μg/ml ruthenylated G2-11 antibody, 4 μg/ml

biotinylated 4G8 antibody diluted in Origen buffer

(Biotinylated 4G8 antibody supplied by Signet Pathology Ltd; G2-10 andG2-11 antibodies supplied by Chemicon)

After overnight incubation of the assay plates on a shaker at 4° C., theOrigen M8 Analyser (Igen Inc.) was calibrated according to themanufacturer's instructions. 25 μl of streptavidin magnetic bead (Dynal)premix (400 μg/ml streptavidin beads/ml in Origen buffer) was added tothe assay plates and incubated on a shaker for 15 minutes. 150 μl Origenbuffer was added to each well and the plates were read on the Origen M8Analyser according to the manufacturer's instructions.

Cell viability was measured in the corresponding cells after removal ofthe media for the Aβ assays by a calorimetric cell proliferation assay(CellTiter 96™ AQ assay, Promega) utilizing the bioreduction of MTS(Owen's reagent) to formazan according to the manufacturer'sinstructions. Briefly, 5 μl of 10× MTS/PES was added to the remaining 50μl of media before returning to the incubator. The optical density wasread at 495 nm after ˜4 hours.

LD₅₀ and IC₅₀ values for inhibition of Aβ(40) and Aβ(42) were calculatedby nonlinear regression fit analysis using the appropriate software (eg.Excel fit). The total signal and the background were defined by thecorresponding Me₂SO and inhibitor controls.

The compounds of the invention give IC₅₀ values for Aβ(1-42) inhibitionthat are at least 2-fold lower than the corresponding IC₅₀ values forAβ(1-40) inhibition, typically at least 5-fold lower, and in thepreferred cases at least 50-fold lower.

EXAMPLES Intermediate 1 (R/S)-1-[4-(trifluoromethyl)phenyl]butan-1-amine

To a solution of 1-[4-(trifluoromethyl)phenyl]butan-1-one (6 g, 27.8mmol) in ethanol (60 ml) was added hydroxylamine hydrochloride (5.79 g,83.3 mmol) and the reaction heated to reflux and stirred for 16 h. Thereaction was allowed to cool to room temperature and then concentratedin vacuo. The residue was taken up in ethyl acetate, washed twice withwater, dried over sodium sulfate and concentrated in vacuo. The crudeoxime was then dissolved in ethanol (100 ml) and Raney nickel (approx 1g) added. The reaction was stirred under a balloon of hydrogen for 72 h.The reaction was filtered though celite (washing with ethanol)concentrated in vacuo, adsorbed onto silica gel and purified by flashcolumn (50-80% ethyl acetate in hexanes) to yield the title compound (5g, 83%) as colourless crystals.

¹H NMR δ(ppm)(CDCl₃): 7.58 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz),3.97 (1H, t, J=6.9 Hz), 1.68-1.60 (2H, m), 1.50 (2H, s), 1.36-1.21 (2H,m), 0.91 (3H, t, J=7.3 Hz).

Intermediate 2 Ethyl (2-pyrrolidin-1-ylcyclohex-2-en-1-yl)acetate

Ethyl 2-cyclohexanone acetate (1 g, 5.43 mmol) was dissolved in toluene(20 ml) and pyrrolidine (0.90 ml, 10.8 mmol, 2 eq.) and acetic acid (0.4ml) added. Dean Stark apparatus was fitted to the flask and the reactionmixture was refluxed for 16 h. The reaction mixture was concentrated invacuo to give a yellow oil (1.4 g). ¹H NMR showed >90% conversion to thetitle compound.

Intermediate 3 3-Phenyl-1-[4-(trifluoromethyl)phenyl]propan-1-amine

Hydroxylamine hydrochloride (2.1 g, 0.03 mol) was added to a solution of3-phenyl-1-[4-(trifluoromethyl)phenyl]propan-1-one (Journal of theAmerican Chemical Society 1994, 116(6), 2312-17, 2.8 g, 0.01 mol) inEtOH (30 ml). The solution was heated to reflux temperature for 18hours. After cooling to RT, the solvent was evaporated under reducedpressure and the residue diluted with EtOAc (30 ml). The organic phasewashed with water (3×20 ml), dried over Na₂SO₄ and concentrated. Thecrude reaction was then dissolved in EtOH (20 ml) and Raney Nickel (5spoons) added. The reaction mixture was stirred for 2 days under aballoon of nitrogen and then filtered through a pad of celite. Thefiltrate was concentrated and purified by chromatography on silica geleluting with 50% AcOEt/Hexane to afford the title compound (0.8 g, 28%);¹H NMR δ (ppm)(CDCl₃, 360 MHz): 7.64 (2H, d, J=7.7 Hz), 7.47 (2H, d,J=7.7 Hz), 7.32 (2H, m), 7.22-7.19 (3H, m), 4.00 (1H, t, J=6.7 Hz),2.73-2.57 (2H, m), 2.07-2.00 (2H, m).

Intermediate 4N-[(1E,2E)-4,4-dimethylpent-2-en-1-ylidene]-2-methylpropane-2-sulfinamide

To a solution of 2-methylpropane-2-sulfinamide (3.08 g, 0.025 mol) indichloromethane (10 ml) was added CuSO₄ (5.42 g, 0.034 mol) followed by(2E)-4,4-dimethylpent-2-enal (Journal of Organic Chemistry 1993, 58(9),2517-22, 1.9 g, 0.017 mol) in dichloromethane (60 ml). The reactionmixture was stirred at RT overnight under nitrogen and then filteredthrough a pad of celite. The filtrate was evaporated under reducedpressure and purified by chromatography on silica gel eluting with 10%AcOEt/Hexane to give 2.1 g (58%) of the title compound; ¹H NMR δ(ppm)(CDCl₃, 400 MHz): 8.19 (1H, d, J=9.2 Hz), 6.53 (1H, d, J=15.7 Hz),6.36 (1H, dd, J=9.2, 15.7 Hz), 1.21 (9H, s), 1.12 (9H, s).

Intermediate 5 4,4-Dimethyl-1-[4-(trifluoromethyl)phenyl]pentan-1-amine

Step 1

Bromo[4-(trifluoromethyl)phenyl]magnesium (0.46M in Et₂O, 20 ml, 9.3mmol) was added dropwise to a solution of intermediate 4 (1.0 g, 4.65mmol) in dichloromethane (20 ml) at −60° C. under nitrogen. The mixturewas allowed to slowly warm to RT (over 3 hours) and then quenched with asaturated solution of NH₄Cl (20 ml). The product was extracted withdichloromethane (20 ml), dried over Na₂SO₄ and concentrated.Purification by chromatography on silica gel eluting with 30%AcOEt/Hexane affordedN-{(2E)-4,4-dimethyl-1-[4-(trifluoromethyl)phenyl]pent-2-en-1-yl}-2-methylpropane-2-sulfinamide(1.2 g, 71%); ¹H NMR δ(ppm)(CDCl₃, 400 MHz): 7.61 (2H, d, J=8.1 Hz),7.46 (2H, d, J=8.1 Hz), 5.83 (1H, dd, J=0.7, 15.6 Hz), 5.38 (1H, dd,J=7.9, 15.6 Hz), 4.97 (1H, dd, J=2.8, 7.9 Hz), 3.42 (1H, bd), 1.23 (9H,s), 1.01 (9H, s).

Step 2

HCl (4.0N in dioxane, 4.1 ml, 0.017 mol) was added to a solution of thesulfinamide from the foregoing step (1.2 g, 3.3 mmol) in dry MeOH (20ml) at 0° C. and the reaction mixture was stirred at that temperaturefor 3 hours. After evaporation of the solvent under reduced pressure,the residue was dissolved in dichloromethane (20 ml), washed with asaturated solution of NaHCO₃ (20 ml), brine (20 ml), dried over Na₂SO₄and concentrated. Purification by chromatography on silica gel elutingwith a gradient 10-25% AcOEt/Hexane afforded(2E)-dimethyl-1-[4-(trifluoromethyl)phenyl]pent-2-en-1-amine (0.62 g,73%); ¹H NMR δ(ppm)(CDCl₃, 360 MHz): 7.58 (2H, d, J=8.2 Hz), 7.47 (2H,d, J=8.2 Hz), 5.70 (1H, dd, J=1.0, 15.5 Hz), 5.47 (1H, dd, J=6.8, 15.5Hz), 4.54 (1H, d, J=6.8 Hz), 1.01 (9H, s).

Step 3

The olefin from the foregoing step (0.1 g, 0.39 mmol) was dissolved inMeOH (5 ml) and Pd/C 10% w (4 mg) was added. The reaction mixture wasstirred for 12 hours in a Parr at 40 PSI. The mixture was filteredtrough a pad of celite and the filtrate was then concentrated underreduced pressure. Purification by chromatography on silica gel elutingwith a gradient 20-50% AcOEt/Hexane afforded the desired4,4-dimethyl-1-[4-(trifluoromethyl)phenyl] pentan-1-amine (90 mg, 89%)as a colourless oil; ¹H NMR δ (ppm)(CDCl₃, 360 MHz): 7.60 (2H, d, J=8.1Hz), 7.45 (2H, d, J=8.1 Hz), 3.91 (1H, t, J=6.8 Hz), 1.67-1.62 (4H, m),0.87 (9H, s).

Intermediate 6 1-[2,4-Bis(trifluoromethyl)phenyl]butan-1-amine

Step 1

A mixture of 2,4-bis trifluoromethyl benzaldehyde (10.0 g, 41.3 mmol),tert butyl sulfinamide (4.5 g, 37.2 mmol) and anhydrous CuSO₄ (13.1 g,82.6 mmol) in DCM (100 ml) was stirred at room temperature overnight.The fine suspension was diluted with water and extracted with DCM. Theextracts were washed with water, dried (MgSO₄) and evaporated in vacuoto afford the desired N-{(1E)-[2,4-bis(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide as an off whitesolid (7.62 g, 53%), with no further purification. ¹H NMR δ(ppm)(CDCl₃):8.99 (1H, d, J=1.9 Hz), 8.35 (1H, d, J=8.2 Hz), 8.02 (1H, s), 7.92 (1H,d, J=8.2 Hz), 1.28 (9H, d, J=4.6 Hz); m/z (ES⁺) 346 (MH⁺).

Step 2

A solution ofN-{(1E)-[2,4-bis(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide(7.62 g, 22.0 mmol) in DCM (50 ml) at −78° C. was treated with^(n)propyl magnesium chloride (2M in DCM, 16.5 ml, 33.1 mmol). Theresultant mixture was allowed to warm to room temperature over 16 hours.NH₄Cl solution (saturated, 80 ml) was added and the solution wasextracted with DCM. The extracts were washed with brine, dried (MgSO₄)and evaporated in vacuo to a yellow oil (3.9 g). The oil was dissolvedin dry methanol (200 ml) cooled to 0° C. and treated with HCl (4N indioxane 10.0 ml, 40.1 mmol). The solution was stirred at 0° C. for 90minutes before the solvent was evaporated in vacuo. The residue was madebasic (NaHCO₃, saturated) and extracted with DCM. The extracts weredried (MgSO₄) and evaporated in vacuo to a yellow oil which was purifiedby chromatography (silica, 10-50% EtOAc/isohexane) to give the amine asa pale oil (1.75 g, 28%); ¹H NMR δ (ppm)(CDCl₃): 7.87 (1H, s), 7.88 (1H,d, J=9.6 Hz), 7.81 (1H, d, J=9.6 Hz), 4.42-4.39 (1H, m), 1.55 (2H, br),1.68 (2H, d, J=7.9 Hz), 1.30-1.16 (2H, m), 0.95-0.89 (3H, m); m/z (ES⁺)286 (MH⁺).

Intermediate 7 1-[2,5-Bis(trifluoromethyl)phenyl]butan-1-amine

Step 1

A mixture of 2,5-bis trifluoromethyl benzaldehyde (21.5 g, 88.8 mmol),tert butyl sulfinamide (16.1 g, 133 mmol) and anhydrous CuSO₄ (16.5 g,103 mmol) in DCM (94 ml) was stirred at room temperature for 16 hoursand at reflux for 3 days. The fine suspension was diluted with water andextracted with DCM. The extracts were washed with water, dried (MgSO₄)and evaporated in vacuo to an off white solid which was purified bychromatography (silica, 4-10% EtOAc/isohexane) to give the desiredN-{(1E)-[2,5-bis(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamideas a white crystalline solid (14.8 g, 91%); ¹H NMR δ(ppm)(CDCl₃): 8.98(1H, d, J=1.8 Hz), 8.46 (1H, s), 7.92-7.85 (2H, m), 1.29 (9H, s); m/z(ES⁺) 346 (MH⁺).

Step 2

A solution ofN-{(1E)-[2,5-bis(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide(6.7 g, 19.4 mmol) in DCM (50 ml) at −78° C. was treated with ^(n)propylmagnesium chloride (2M in DCM, 15 ml, 29 mmol) using the procedure ofIntermediate 6, step 2, to give the desired amine as a pale oil (5.1 g,94%). ¹H NMR δ (ppm)(CDCl₃): 8.02 (1H, s), 7.74 (1H, d, J=8.2 Hz), 7.59(1H, d, J=8.3 Hz), 4.43-4.41 (1H, m), 1.72 (2H, br), 1.68 (2H, d, J=7.9Hz), 1.30-1.16 (2H, m), 0.95-0.89 (3H, m); m/z (ES⁺) 286 (MH⁺).

Intermediate 8 (1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}amine

Step 1

Magnesium (17 g) was stirred 10 mins under nitrogen then tetrahydrofuran(400 ml) was added. A 5 ml portion of bromomethylbutane was added andthe mixture stirred 5 minutes until the reaction initiated (exotherm)the reminder of the bromomethylbutane (100 g, 0.672 mol) was addedkeeping the temp below 35° C. (water bath). The mixture was stirred 1 hrat rt and a solution of 4-CF₃-benzonitrile (10 g, 0.584 mol) in toluene(11) containing some CuBr was added dropwise keeping the temp 25° C. Thesolution was stirred 1 h and quenched carefully with 15% H₂SO₄(exotherm). The organic layer was decanted, washed with brine, driedover MgSO₄ and concentrated in vacuo. The oil was purified by columnchromatography on silica using isohexane as eluent to give4-methyl-1-[4-(trifluoromethyl)phenyl]pentan-1-one (126 g) whichsolidified on standing. ¹H NMR 8 (ppm)(CDCl₃): 8.06 (2H, d, J=8.1 Hz),7.73 (2H, d, J=8.1 Hz), 2.99 (2H, app. t, J=7.4 Hz), 1.68-1.60 (3H, m),0.96 (6H, d, J=6.3 Hz).

Step 2

To a solution of 4-methyl-1-[4-(trifluoromethyl)phenyl]pentan-1-one (70g, 0.312 mol) in toluene (500 ml) at room temperature was addedS-phenylethylamine (44.5 g, 0.374 mol) and zinc chloride (2 g, 15.61mmol). A Dean Stark apparatus was attached and the reaction refluxed for16 h. The reaction was cooled down, washed with 1N NaOH (800 ml), threetimes with saturated ammonium chloride, dried over magnesium sulfate andevaporated to give 4-methyl-1-[4-(trifluoromethyl)phenyl]pentylidene}[(1S)-1- phenylethyl]amine (87 g) as a 3:1 mixture of isomers as an oilthat was taken directly into Step 3.

Step 3

To a solution of 4-methyl-1-[4-(trifluoromethyl)phenyl]pentylidene}[(1S)-1-phenylethyl]amine (87 g, 0.25 mol) in methanol (0.51) at −20° C.was added sodium borohydride (10 g, 0.263 mol) portionwise. The solutionwas stirred ½ hrs at 0° C. and quenched carefully with 1N HCl, basifiedwith 4N NaOH and extracted with ethyl acetate. The organic layer wasdecanted, dried (MgSO₄) and evaporated to give 85 g of4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}[(1S)-1-phenylethyl] amineas a 3/1 mixture of diastereomers by NMR. This was dissolved in methanol(250 ml) and phthalic acid (40 g) was added. The solution was stirred atroom temperature when it started to crystallise. The mixture was stirred2 hrs at room temperature and the solid was then filtered to give singlediastereomer {(1R)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}[(1S)-1-phenylethyl] amine as the phthalic acid salt (70.5 g). A smallportion of the phthalic acid salt was partitioned between CDCl₃ andaqueous K₂CO₃ to form the free base and a ¹H NMR was taken; ¹H NMR 6(ppm)(CDCl₃): 7.57 (2H, d, J=8.0 Hz), 7.33 (5H, dd, J=7.6, 9.8 Hz), 7.16(2H, d, J=6.9 Hz), 3.40 (1H, q, J=6.7 Hz), 3.32 (1H, t, J=6.9 Hz),1.66-1.48 (2H, m), 1.46-1.32 (1H, m), 1.26 (3H, d, J=6.7 Hz), 1.19-1.09(1H, m), 0.95-0.85 (1H, m), 0.79 (3H, d, J=3.6 Hz), 0.77 (3H, d, J=3.5Hz).

Step 4

A suspension of{(1R)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}[(1S)-1-phenylethyl]amine phthalate salt (70 g, 0.135 mol) and 10% palladium on carbon (900mg) in EtOH (300 ml) was hydrogenated under 40 psi at 57° C. for 3.5 h.The catalyst was filtered and the solution concentrated to a half. Theorganic was diluted with ethyl acetate, washed three times with 4N NaOHthen with brine, dried (MgSO₄) and evaporated to give the title compoundas a liquid (60 g); ¹H NMR δ (ppm)(CDCl₃): 7.58 (2H, d, J=8.2 Hz), 7.43(2H, d, J=8.0 Hz), 3.93 (1H, t, J=6.8 Hz), 1.69-1.59 (2H, m), 1.57-1.49(1H, m), 1.28-1.18 (1H, m), 1.11-1.01 (1H, m), 0.87 (3H, d, J=1.8 Hz),0.85 (3H, d, J=1.8 Hz); m/z (ES⁺) 246 (M+H⁺). α_(D) ²⁰=−9.0 (c=1,CHCl₃).

The enantiomer (+)-{(1R)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}amine was prepared by analogy to intermediate 8 but employingR-phenylethylamine instead of S-phenylethylamine in Step 2.

Intermediate 9 {(1S)-1-[4-(trifluoromethyl)phenyl]butyl} amine

{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}amine was prepared by analogyto Intermediate 8, by use of n-propylbromide in Step 1; ¹H NMRδ(ppm)(CDCl₃): 7.58 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 3.97 (1H,t, J=6.9 Hz), 1.68-1.60 (2H, m), 1.50 (2H, s), 1.36-1.21 (2H, m), 0.91(3H, t, J=7.3 Hz).

Intermediate 10 {(1R)-1-[4-(trifluoromethyl)phenyl]butyl} amine

{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}amine was prepared asintermediate 9 employing R-phenylethylamine instead ofS-phenylethylamine in Step 2; ¹H NMR δ (ppm)(CDCl₃): 7.58 (2H, d, J=8.1Hz), 7.43 (2H, d, J=8.1 Hz), 3.97 (1H, t, J=6.9 Hz), 1.68-1.60 (2H, m),1.50 (2H, s), 1.36-1.21 (2H, m), 0.91 (3H, t, J=7.3 Hz).

Intermediate 11 {(1R)-1-[4-(trifluoromethyl)phenyl]pentyl}amine

{(1R)-1-[4-(trifluoromethyl)phenyl]pentyl}amine was prepared by analogyto Intermediate 8, by use of n-butylbromide in Step 1 and employingR-phenylethylamine instead of S-phenylethylamine in Step 2; ¹H NMRδ(ppm)(CDCl₃): 7.55 (2H, d, J=8.2 Hz), 7.43 (2H, d, J=8.2 Hz), 3.95 (1H,t, J=6.9 Hz), 1.71-1.67 (2H, m), 1.37-1.13 (4H, m), 0.87 (3H, t, J=7.1Hz).

Intermediate 12 (2R,3S)-2-allyl-3-ethylcyclohexanone

Prepared according to Chem. Comm., 2001, 735-736

Intermediate 13 [(1R,2S-2-ethyl-6-oxocyclohexyl]acetic acid

To a bi-phasic solution of intermediate 12 (1.09 g, 6.57 mmol) andsodium periodate (5.76 g, 26.93 mmol) in carbon tetrachloride (13 ml),acetonitrile (13 ml) and water (19.5 mL) was added ruthenium trichloridemonohydrate (32 mg, 8.14 mmol). The resulting heterogeneous solution wasstirred at ambient temperature for 16 h. The reaction mixture wasdiluted with dichloromethane (100 ml) and filtered through hyflosupercel. The filtrate was partitioned between dichloromethane andaqueous. The aqueous layer was further extracted with dichloromethane(5×50 ml). The combined organic extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo to give the title compound as anoil (1.0 g, 83%) ¹H NMR δ (ppm)(400 MHz, CDCl₃): 9.84-9.79 (s, 1H),2.87-2.74 (m, 1H), 2.72-2.62 (m, 1H), 2.46-2.32 (m, 3H), 2.14-2.04 (m,1H), 1.99-1.97 (m, 1H), 1.67-1.41 (m, 4H), 1.38-1.23 (m, 1H), 0.94-0.90(m, 3H).

Intermediate 14 Ethyl [(1R,2S)-2-ethyl-6-oxocyclohexyl]acetate

A catalytic amount of concentrated hydrochloric acid was added into asolution of intermediate 13 (1.0 g, 5.43 mmol) in ethanol (50 ml). Theresulting solution was stirred at reflux for 16 h. The reaction mixturewas concentrated in vacuo and the residual oil was purified by flashchromatography eluting with 10% ethyl acetate in hexane to afford ethyl[(1R,2S)-2-ethyl-6-oxocyclohexyl]acetate as a colourless oil (911 mg,80%). ¹HNMR δ (ppm)(400 MHz, CDCl₃): 4.16-4.09 (2H, m), 2.70-2.61 (2H,m), 2.44-2.32 (m, 3H), 2.13-2.07 (m, 1H), 1.97-1.91 (m, 1H), 1.65-1.34(m, 3H), 1.33-1.21 (m, 5H), 0.93 (t J 7.4 Hz, 3H)

Intermediate 15 (2E)-4,4-dimethylpent-2-en-1-ol

Prepared as in J Org. Chem. 2003, 68(8), 3130-3138. ¹H NMR δ (ppm)(400MHz, CDCl₃): ¹H NMR δ (ppm)(CDCl₃): 5.71 (1H, d, J=15.9 Hz), 5.54 (1H,dt, J=15.9, 6.0 Hz), 4.10 (2H, d, J=6.0 Hz), 1.02 (9H, s).

Intermediate 16 2-Isopropylprop-2-en-1-ol

Prepared according to the procedure described in J. Organomet. Chem.1979, 168(1), 1-11. ¹H NMR δ (ppm)(400 MHz, CDCl₃): ¹H NMR δ(ppm)(CDCl₃): 5.00 (1H, d, J=1.2 Hz), 4.90 (1H, t, J=1.0 Hz), 4.13 (2H,s), 2.36-2.28 (1H, m), 1.43 (1H, s), 1.07 (6H, d, J=6.9 Hz).

Intermediate 17 2-cyclohexylprop-2-en-1-ol

Prepared according to the procedure described in J. Organomet. Chem.1979, 168(1), 1-11. ¹H NMR δ (ppm)(400 MHz, CDCl₃): 5.00 (1H, s), 4.87(1H, s), 4.11 (2H, s), 1.95 (1H, t, J=11.2 Hz), 1.74-0.90 (10H, m).

Intermediate 18 2-[4-(trifluoromethyl)phenyl]prop-2-en-1-ol

Prepared according to the procedure described in J. Organomet. Chem.1979, 168(1), 1-11. ¹H NMR δ (ppm)(400 MHz, CDCl₃): 7.58 (4H, q, J=8.6Hz), 5.55 (1H, s), 5.46 (1H, s), 4.53 (2H, dd, J=0.0, 5.9 Hz), 1.77 (1H,t, J=6.0 Hz).

Intermediate 19 (2E)-3-(2,4-dichlorophenyl)prop-2-en-1-ol

Step 1

To a stirred solution of (2E)-3-(2,4-Dichlorophenyl)acrylic acid (10 g,46 mmol) in ethanol (60 ml) was added conc. H₂SO₄ (2.5 ml). The mixturewas heated to reflux and for 48 h, then allowed to cool, concentrated invacuo, dissolved in ethyl acetate, washed three times with 4N NaOH,dried over sodium sulfate and concentrated in vacuo to afford ethyl(2E)-3-(2,4-dichlorophenyl)acrylate (10.7 g) as pale brown crystals.¹HNMR δ (ppm)(CDCl₃): 8.00 (1H, d, J=16.1 Hz), 7.55 (1H, d, J=8.5 Hz),7.44 (1H, d, J=1.9 Hz), 7.26 (1H, dd, J=2.0, 8.4 Hz), 6.41 (1H, d,J=16.1 Hz), 4.28 (2H, q, J=7.1 Hz), 1.34 (3H, t, J=7.1 Hz).

Step 2

To a stirred solution of ethyl (2E)-3-(2,4-dichlorophenyl)acrylate (11.3g, 46 mmol) in tetrahydrofuran at −10° C. was added diisobutylaluminiumhydride (1.0 M in toluene, 100 ml, 0.11 mol) dropwise. After additionwas complete, the reaction was cooled to −78° C. and methanol (40 ml)added dropwise. Ammonium chloride (sat. aq., 70 ml) was then added andthe reaction allowed to warm to 0° C. After 15 min at 0° C. the reactionwas allowed to warm to room temperature and stirred for 1 h. The mixturewas then filtered through a pad of hyflo supercel (washing well withethyl acetate) and the concentrated to give the title compound (7.8 g)as pale yellow crystals. ¹H NMR δ (ppm)(CDCl₃): 7.44 (1H, d, J=8.4 Hz),7.36 (1H, d, J=2.0 Hz), 7.19 (1H, dd, J=2.0, 8.5 Hz), 6.93 (1H, d,J=15.8 Hz), 6.36-6.28 (1H, m), 4.35 (2H, d, J=5.4 Hz), 1.84 (1H, s).

Intermediate 20 (2E)-3-(4-Chlorophenyl)-2-isopropylprop-2-en-1-ol

Prepared according to a procedure described in PCT Int. Appl. (2002), 34pp., WO 2002002487. ¹H NMR δ (ppm)(CDCl₃): 7.30 (2H, d, J=8.4 Hz), 7.15(2H, d, J=8.4 Hz), 6.49 (1H, s), 4.30 (2H, s), 3.07-2.99 (1H, m), 1.09(6H, d, J=7.0 Hz).

Intermediate 21 Mixture of Ethyl (2-ethoxycyclohex-2-en-1-yl)acetate andethyl (2,2-diethoxycyclohexyl)acetate

To a stirred solution of ethyl (2-oxocyclohexyl)acetate (40.2 ml, 0.228mol) in ethanol (66 ml) was added p-toluenesulfonic acid (422 mg, 2.28mmol) and triethylorthoformate (113 ml, 0.684 mol). The reaction mixturewas heated to 95° C. and stirred for 16 h. The mixture was concentratedin vacuo at 60 oC for 2½ hours to remove triethylorthoformate. Themixture was used crude in subsequent reactions. ¹H NMR δ (ppm)(CDCl₃):4.60 (1H, t, J=3.9 Hz), 4.17-4.09 (4H, m), 3.76-3.58 (4H, m), 3.47-3.41(3H, m), 3.11 (1H, s), 2.71-2.63 (2H, m), 2.58-2.40 (1H, m), 2.37-2.09(4H, m), 2.07-1.97 (4H, m), 1.91-1.33 (8H, m), 1.31-1.16 (14H, m).

Intermediate 22{(1R)-3-methyl-1-[4-(trifluoromethyl)phenyl]butan-1-amine

{(1R)-3-methyl-1-[4-(trifluoromethyl)phenyl]butan-1-amine was preparedby analogy to Intermediate 8, by use of i-butylbromide in Step 1 andemploying R-phenylethylamine instead of S-phenylethylamine in Step 2; ¹HNMR δ (ppm)(CDCl₃): 7.58 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.2 Hz), 4.03(1H, t, J=6.8 Hz), 1.34-1.22 (3H, m), 0.93 (3H, d, J=6.3 Hz), 0.91 (3H,d, J=6.3 Hz).

Intermediate 23 {1-[4-(trifluoromethyl)phenyl]butyl}hydrazine

Hydrazine monohydrate (8.9 g) was dissolved in isopropanol (25 ml) and1-(1-bromobutyl)-4-(trifluoromethyl)benzene (as prepared in WO2005013985, 2.0 g, 7.12 mmol) added. The mixture was heated to 70° C.and stirred for 16 h. After this time the solvent was removed and theresidue taken up in ethyl acetate and washed three times (H₂O). Thecombined organics were dried (sodium sulfate) and concentrated to givethe mixture of products as a white solid suspended in a clear oil. Themixture was triturated with diethyl ether to give a white solid; ¹H NMRδ (ppm)(DMSO): 9.20 (1H, s), 7.76 (2H, d, J=8.1 Hz), 7.64 (2H, s), 4.16(1H, s), 1.85 (1H, s), 1.59 (1H, s), 1.20-0.96 (2H, m), 0.82 (3H, t,J=7.3 Hz).

Example 1(3-phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Step 1

Ethyl 2-cyclohexanoneacetate (0.34 ml, 1.92 mmol) was added to asolution of Intermediate 1 (418 mg, 1.92 mmol) in toluene (10 ml) in aflask fitted with Dean-Stark apparatus. The reaction was heated toreflux under N₂ for 16 h, then allowed to cool to room temperature. Theresulting solution of ethyl[(2E)-2-({1-[4-(trifluoromethyl)phenyl]butyl}imino)cyclohexyl]acetate intoluene was used directly in the next step.

Step 2

Trans-beta-nitrostyrene (286 mg, 1.92 mmol) was added to the reactionmixture, the Dean-Stark trap was replaced with a reflux condenser andthe reaction heated at reflux for 40 h. After cooling, the reaction wasdiluted with ethyl acetate, washed with saturated sodium bicarbonatesolution and twice with water, then dried over sodium sulfate andconcentrated in vacuo. The product was purified by mass directed HPLC togive ethyl(3-phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetate(107 mg, 11%), a colourless oil as a 1:1 mixture of diastereomers.

Step 3

To a stirred solution of ethyl(3-phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetate(107 mg, 2.2 mmol) in dioxane (5 ml) and water (0.5 ml) was addedlithium hydroxide (900 mg, 22.0 mmol) and the reaction heated to refluxfor 16 h. After cooling, the reaction was diluted with ethyl acetate andacidified with 2N HCl. The aqueous layer was extracted three times withethyl acetate, and the combined organic layers dried over sodium sulfateand concentrated in vacuo. The product was purified by mass directedHPLC to give(3-phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid (55.1 mg, 55%), a colourless foam as a 1:1 mixture of diastereomersA and B; ¹H NMR δ (ppm) (CDCl₃): 7.59 (2H, d, J=8.2 Hz, A/B), 7.53 (2H,d, J=8.1 Hz, A/B), 7.47 (2H, d, J=8.1 Hz, A/B), 7.35 (4H, t, J=7.3 HzA+B), 7.21-7.13 (4H, m, A+B), 7.06 (1H, s, A), 6.95 (1H, s, B),5.19-5.11 (2H, m, A+B), 3.39 (1H, d, J=9.0 Hz, B), 3.06 (1H, s, A),2.79-2.65 (5H, m, A+B), 2.37-2.19 (2H, m, A+B), 2.14-2.08 (4H, m, A+B),2.00 (1H, s, A/B), 1.90-1.78 (6H, t, J=13.5 Hz, A+B), 1.74-1.70 (4H, m,A+B), 1.42 (1H, t, J=6.1 Hz, A/B), 1.38-1.30 (1H, m A/B), 1.03 (3H, t,J=7.3 Hz, A/B), 0.95 (3H, t, J=7.3 Hz, A/B); m/z (ES⁻) 454 (M−H⁺).

Example 2(3-(2,4-Dichlorophenyl)-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared as described for Example 1, using2,4-dichloro-beta-nitrostyrene in Step 2 with heating at 200° C. in amicrowave apparatus; m/z (ES⁻) 522 (M−H⁺). The enantiomers anddiastereomers could be separated by supercritical fluid chromatography.A CHIRALPAK AD-H column 250×10 mm (5 μl) Column temperature 40° C.,Mobile phase: 85/15 CO₂/MeOH, Flow rate: 10 mL/min, outlet pressure 100bar gave pure Example 2a((7S)-3-(2,4-dichlorophenyl)-1-{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid eluting at 5.50 min ¹H NMR δ(ppm) (CDCl₃): 7.55 (2H, d, J=8.2 Hz),7.46 (1H, d, J=2.0 Hz), 7.29 (1H, s), 7.22 (1H, dd, J=2.1, 8.3 Hz), 7.14(2H, d, J=8.1 Hz), 7.04 (1H, s), 5.14 (1H, dd, J=6.3, 9.0 Hz), 3.04 (1H,s), 2.66 (2H, d, J=6.7 Hz), 2.42 (2H, t, J=3.7 Hz), 2.24-2.16 (1H, m),2.11-2.04 (1H, m), 1.81-1.66 (5H, m), 1.42 (1H, dd, J=0.0, 6.6 Hz), 1.21(3H, d, J=6.1 Hz), 1.01 (3H, t, J=7.3 Hz), a mixture of Example 2b((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid and Example 2c((7R)-3-(2,4-dichlorophenyl)-1-{(1S-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid eluting at 6.25 min and finally pure Example 2d((7R)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid eluting at 7.35 min ¹H NMR δ (ppm) (CDCl₃): 7.55 (2H, d, J=8.2 Hz),7.46 (1H, d, J=2.0 Hz), 7.29 (1H, s), 7.22 (1H, dd, J=2.1, 8.3 Hz), 7.14(2H, d, J=8.1 Hz), 7.04 (1H, s), 5.14 (1H, dd, J=6.3, 9.0 Hz), 3.04 (1H,s), 2.66 (2H, d, J=6.7 Hz), 2.42 (2H, t, J=3.7 Hz), 2.24-2.16 (1H, m),2.11-2.04 (1H, m), 1.81-1.66 (5H, m), 1.42 (1H, dd, J=0.0, 6.6 Hz), 1.21(3H, d, J=6.1 Hz), 1.01 (3H, t, J=7.3 Hz). The mixture of Example 2b andExample 2c were separated by further SFC purification using a CHIRALCELOJ-H column 250×10 mm (5□) Column temperature 40° C., Mobile phase:80/20 CO₂/MeOH, Flow rate: 10 mL/min, outlet pressure 100 bar gaveExample 2b((7R)-3-(2,4-dichlorophenyl)-1-{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid eluting at 3.04 min ¹H NMR δ (ppm)(CDCl₃): 7.59 (2H, d, J=8.1 Hz),7.46 (1H, d, J=1.8 Hz), 7.32 (2H, d, J=8.1 Hz), 7.30 (1H, d, J=8.3 Hz),7.22 (1H, dd, J=8.3, 1.8 Hz), 6.96 (1H, s), 5.18 (1H, t, J=7.6 Hz), 3.38(1H, d, J=8.5 Hz), 2.48-2.43 (2H, m), 2.29 (1H, dd, J=11.0, 15.6 Hz),2.12-2.06 (2H, m), 2.03 (1H, d, J=15.6 Hz), 1.88-1.76 (3H, m), 1.68 (1H,m), 1.38-1.30 (2H, m), 0.96 (3H, t, J=7.3 Hz) and Example 2c((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 4.13 min¹H NMR δ (ppm)(CDCl₃): 7.59 (2H, d, J=8.1 Hz), 7.46 (1H, d, J=1.8 Hz),7.32 (2H, d, J=8.1 Hz), 7.30 (1H, d, J=8.3 Hz), 7.22 (1H, dd, J=8.3, 1.8Hz), 6.96 (1H, s), 5.18 (1 H, t, J=7.6 Hz), 3.38 (1H, d, J=8.5 Hz),2.48-2.43 (2H, m), 2.29 (1H, dd, J=11.0, 15.6 Hz), 2.12-2.06 (2H, m),2.03 (1H, d, J=15.6 Hz), 1.88-1.76 (3H, m), 1.68 (1 H, m), 1.38-1.30(2H, m), 0.96 (3H, t, J=7.3 Hz).

Examples 3-16

Following the procedures of Examples 1 and 2, using the appropriatenitroalkene in Step 2, the following were prepared: Mass Example R¹Spec. (M − H⁺) 3 4-isopropylphenyl 496 4 4-methylphenyl 468 52,6-dichlorophenyl 522 6 2-CF₃-phenyl 522 7 2-chlorophenyl 488 84-chlorophenyl 488 9 2-bromophenyl 533 10 3-CF₃-phenyl 522 113,4-dichlorophenyl 522 12 3,5-dichlorophenyl 522 13 2,3-dichlorophenyl522 14 2,5-dichlorophenyl 522 15 2-Br-4-Cl-phenyl 567 16 5-Cl-2-thienyl495

When not available commercially, the nitroalkenes were prepared bypublished methods, e.g. base-catalysed condensation of R¹CHO withnitromethane.

Example 17(3-(2-butyl-4-chlorophenyl)-1-{1-[4-(trifluoromethyl)phenyl]butyl}-hydro-1H-indol-7-yl)aceticacid

Ethyl(3-(2-bromo-4-chlorophenyl)-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetraydro-1H-indol-7-yl)acetate(prepared using the procedures of example 1, steps 1 and 2 using2-bromo-4-chloro-1-[(E)-2-nitrovinyl]benzene in place of[(E)-2-nitrovinyl]benzene in step 1) (41 mg, 0.068 mmol) was dissolvedin toluene (2 ml) and water (1 ml) and n-butylboronic acid (9 mg, 0.088mmol), K₃PO₄ (51 mg, 0.24 mmol), tricylohexylphosphine (2 mg, 0.007mmol), and palladium acetate (2 mg, 0.007 mmol) added. The mixture wasdegassed for 5 min, then heated to 100° C. and stirred for 2 h 30 min.The reaction was then allowed to cool, then diluted with water andextracted twice with ethyl acetate. The combined organics were washedwith brine, dried over sodium sulfate, concentrated in vacuo andpurified by column chromatography (1-10% EtOAc/Hexanes) to give thedesired ester (12 mg) as a colourless oil.

This ester was hydrolysed following the procedure in Example 1 Step 3 toafford the desired acid; m/z (ES⁻) 544 (M-H⁺).

Example 18(3-(2-(2-methylpropyl)-4-chlorophenyl)-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared by analogy to example 17 using 2-methylpropylboronic acid inplace of n-butylboronic acid; m/z (ES⁻) 544 (M−H⁺).

Example 19(2-Phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Step 1-Ethyl [2-oxo-3-(2-oxo-2-phenylethyl)cyclohexyl]acetate

Intermediate 2 (667 mg, 2.81 mmol) was dissolved in dimethylformamide(14 ml), 2-bromo-1-phenylethanone (560 mg, 2.81 mmol) was added and thereaction stirred for 24 h at room temperature. Water (5 ml) was addedand the reaction allowed to stir for a further 24 h. The mixture wasthen diluted with ethyl acetate (100 ml) and washed with water. Theaqueous fraction was re-extracted three times with ethyl acetate and thecombined organic fractions washed three times with water, then driedover sodium sulfate, filtered and concentrated in vacuo. Columnchromatography (10-20% ethyl acetate/hexanes) provided the titlecompound as a pale yellow oil (428 mg, 50%).

Step 2

The product of Step 1 (274 mg, 0.907 mmol), Intermediate 1 (195 mg,0.907 mmol), acetic acid (0.1 ml) and toluene (10 ml) were refluxed for16 hours in a Dean Stark apparatus. The reaction mixture was allowed tocool to RT, concentrated in vacuo, absorbed onto silica gel thenpurified by flash column chromatography (10% ethyl acetate/hexanes) toafford a colorless oil (35 mg, 8%) This product was hydrolysed by themethod of example 1 Step 3 and purified by column chromatography (10-20%ethyl acetate/hexanes) to give the title compound, a colourless oil(18.3 mg, 55%) as a 2:1 mixture of diastereomers (designated isomers Aand B respectively). ¹H NMR δ (ppm) (CDCl₃): 7.56 (3H, d, J=8.3 Hz,A+B), 7.49 (1H, d, J=8.2 Hz A/B), 7.32-6.98 (14H, m), 5.96 (1H, s, B),5.93 (1H, s, A), 5.32-5.22 (2H, m), 3.22 (1H, d, J=10.9 Hz A), 3.10-2.96(1H, m, B), 2.69-2.49 (4H, m, A+B), 2.40-2.26 (2H, m, A+B), 2.22-2.08(2H, m, A+B), 2.03-1.89 (2H, m, A+B), 1.86-1.71 (7H, m, A+B) 1.6-1.1(7H, A+B) 0.97-0.78 (6H, m, A+B); m/z (ES⁻) 454 (M−H⁺).

Example 20(2-(2,4-dichlorophenyl)-1-{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared analogously to example 19, using2-bromo-1-(2,4-dichlorophenyl)ethanone in step 1, desired product wasobtained; m/z (ES⁻) 522 (M−H⁺).

Example 21 Example 21a((7R)-2-tert-butyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid and Example 21b((7S)-2-tert-butyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid

Step 1

Ethyl [3-(3,3-dimethyl-2-oxobutyl)-2-oxocyclohexyl]acetate

Prepared using procedure of Example 19 Step 1, using1-bromo-3,3-dimethylbutan-2-one.

Step 2

A stirred solution of ethyl[3-(3,3-dimethyl-2-oxobutyl)-2-oxocyclohexyl]acetate (415 mg, 1.47 mmol)and {(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}amine (432 mg,1.76 mmol) in dichloromethane (10 ml) was cooled to −78° C. andtriethylamine (1.2 ml, 8.82 mmol) then titanium tetrachloride (0.32 ml,2.94 mmol) were added dropwise. The reaction became instantly dark brownon addition of titanium tetrachloride. The reaction was allowed to warmslowly to room temperature and then stirred for 16 h. The reactionmixture was quenched with saturated aqueous sodium bicarbonate,extracted three times with ethyl acetate, dried over sodium sulfate andpurified by chromatography on silica gel eluting with 1-5% ethylacetate/hexane afforded impure ethyl(2-tert-butyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetate(251 mg) which was taken into the next step without furtherpurification; m/z (ES⁺) 492 (M+H⁺).

Step 3

The product from the foregoing step was dissolved in methanol (3 ml) andwater (1 ml) and KOH (500 mg) added. The reaction mixture was heated toreflux and stirred for 16 h. After cooling, the reaction was quenchedwith 2N HCl and extracted three times with ethyl acetate, dried oversodium sulfate concentrated in vacuo and purified by chromatography onsilica gel eluting with 20% ethyl acetate/hexane. Unhydrolysed startingester (150 mg) was also recovered. The product was then further purifiedby Agilent mass directed HPLC, which also separated the diastereomers.((7R)-2-tert-butyl-1-{(159-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

¹H NMR δ (ppm) (CDCl₃): 7.55 (2H, d, J=8.2 Hz), 7.34 (2H, d, J=8.2 Hz),5.80 (1H, s), 5.62 (1H, t, J=7.4 Hz), 3.11 (1H, d, J=10.8 Hz), 2.57-2.45(3H, m), 2.10-2.02 (1H, m), 1.95 (1H, dd, J=11.5, 17.0 Hz), 1.71-1.62(3H, m), 1.40 (9H, s), 1.34-1.24 (3H, m), 1.16-1.04 (2H, s), 0.98-0.82(6H, m); m/z (ES⁻) 462 (M−H⁺).((7S)-2-tert-butyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

¹H NMR δ (ppm) (CDCl₃): 7.50 (2H, d, J=8.3 Hz), 6.82 (2H, d, J=8.2 Hz),5.80 (1H, s), 5.53 (1H, s), 2.64-2.52 (3H, m), 2.25-2.13 (1H, m),2.02-1.98 (1H, m), 1.74-1.54 (6H, t, J=6.2 Hz), 1.41-1.38 (1H, m), 1.34(9H, s), 1.21-1.13 (1H, m), 1.16 (1H, d, J=7.2 Hz), 1.00 (3H, d, J=6.3Hz), 0.96 (3H, d, J=6.3 Hz); m/z (ES) 462 (M−H⁺).

Example 22(2-Methyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Step 1-Ethyl (2-oxo-3-prop-2-yn-1-ylcyclohexyl)acetate

Intermediate 2 (1.4 g, 6 mmol) was dissolved in toluene (7 ml) andpropargyl bromide (80% wt in toluene, 7 ml) was added. The reaction washeated to 80° C. and stirred at this temperature for 16 h. Water (5 ml)was then added and the reaction refluxed for a further 2 h. Aftercooling, 2N HCl was added, and the mixture extracted three times withethyl acetate, dried over sodium sulfate, filtered, concentrated invacuo and purified by column chromatography (2.55-10% EtOAc/hexanes).The title compound was obtained as a 1:1 inseparable mixture with ethyl2-cyclohexanoneacetate (550 mg).

Step 2

The product from Step 1 (250 mg) was dissolved in toluene (15 ml) andIntermediate 1 (300 mg) and acetic acid (1 drop) added. A Dean Starkapparatus was fitted and the reaction heated to reflux for 16 h. Thereaction mixture was allowed to cool, concentrated in vacuo and purifiedby column chromatography to afford a colourless oil (13 mg). Thisproduct was hydrolysed by the method of Example 1 Step 3 and purified bycolumn chromatography (10-30% EtOAc/hexanes) to give the title compound,a colourless oil (6.2 mg), as a 1.8:1 mixture of diastereomers. ¹H NMR δ(ppm)(CDCl₃): 7.54 (4H, m, A+B), 7.15 (2H, d, J=8.2 Hz, A), 7.03 (2H, d,J=7.9 Hz, B), 5.72 (1H, s, A), 5.69 (1H, s, B), 5.30-5.15 (2H, m, A+B),3.26 (2H, m, A+B), 2.55-2.40 (4H, m), 2.38-2.28 (2H, m), 2.26-2.20 (2H,m), 2.16-2.06 (2H, m), 2.02 (3H, s, B), 1.86 (3H, s, B), 1.84-1.74 (4H,m), 1.58-1.52 (2H, m) 1.40-0.80 (14H, m).

Example23-(2-Ethyl-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Step 1-Ethyl {3-[(2E)-but-2-en-1-yl]-2-oxocyclohexyl}acetate

Intermediate 2 (6.4 g, 27 mmol) was dissolved in dimethylformamide (100ml) and crotyl bromide (12 g, 90 mmol) was added. The reaction stirredat room temperature for 16 h. Water (24 ml) was then added and thereaction stirred for a further 5 d. Water (100 ml) was then added, andthe mixture extracted three times with ethyl acetate, the combinedorganic phases washed three times with water, dried over sodium sulfate,filtered, concentrated in vacuo and purified by column chromatography(5-10% EtOAc/hexanes). The title compound (1.3 g) was obtained as acolourless oil as a mixture of diastereomers. ¹H NMR δ (ppm)(CDCl₃):5.49-5.33 (2H, m), 4.13 (2H, q, J=7.1 Hz), 2.92-2.74 (2H, m), 2.48-2.32(2H, m), 2.21-2.11 (3H, m), 1.92-1.70 (3 H, m), 1.67-1.58 (3H, m),1.41-1.23 (5H, m).Step 2-Ethyl (2-ethyl-7a-hydroxyoctahydro-1-benzofuran-7-yl)acetate

To a stirred solution of ethyl{3-[(2E)-but-2-en-1-yl]-2-oxocyclohexyl}acetate (565 mg, 2.37 mmol) intetrahydrofuran (20 ml) at 0° C. was added borane.tetrahydrofurancomplex (1 M in tetrahydrofuran, 3.56 ml, 3.56 mmol) and the reactionallowed to stir at 0° C. for 35 min. Sodium hydroxide (4N, 5.6 ml) andhydrogen peroxide (5.6 ml) were added and the reaction allowed to stirat room temperature for 1 h. Diluted with brine, then extracted threetimes with dichloromethane. The combined organics were washed twice withbrine, dried over sodium sulfate, concentrated in vacuo and purified bycolumn chromatography (50% EtOAc/hexanes). The desired title compound(345 mg) was obtained as a colourless oil as a complex mixture ofdiastereomers.Step 3-Ethyl [2-oxo-3-(2-oxobutyl)cyclohexyl]acetate

To a stirred solution of ethyl(2-ethyl-7α-hydroxyoctahydro-1-benzofuran-7-yl)acetate (345 mg, 1.34mmol) in dichloromethane (12 ml) was added pyridine (0.5 ml) andDess-Martin Periodinane (85.7 mg, 2.02 mmol). After 4 h, the reactionwas quenched with a 1:1 mixture of NaHCO₃ (sat aq) and Na₂S₂O₃ (1M,aq.), extracted three times with ethyl acetate, dried over sodiumsulfate, concentrated in vacuo, and purified by column chromatography(10-30% EtOAc/hexanes). The desired title compound (211 mg) was obtainedas a colourless oil; ¹H NMR δ (ppm)(CDCl₃): 3.63 (2H, q, J=7.1 Hz),2.59-2.39 (3H, m), 2.25 (1H, dd, J=6.6, 16.5 Hz), 2.10-1.86 (2H, m),1.71-1.67 (3H, m), 1.39-1.29 (2H, m), 1.14 (1H, t, J=10.2 Hz), 0.96-0.82(2H, m), 0.78-0.68 (3H, m), 0.56 (3H, t, J=7.3 Hz).

Step4-(2-Ethyl-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Using the diketone from the foregoing step and the procedure fromexample 22, step 2 (employing intermediate 10) followed by the procedurefrom example 1, step 3 afforded the title compound (9.6 mg) as a mixtureof diastereomers, ¹H NMR δ (ppm)(CDCl₃): 7.56-7.51 (2H, m), 7.14 (1H, d,J=8.0 Hz), 7.04 (1H, s), 5.81 (1H, s), 5.76 (1H, s), 5.20 (1H, d, J=7.5Hz), 3.19 (1H, d, J=11.8 Hz), 2.53-2.30 (5H, m), 2.30-2.08 (3H, m), 1.83(1H, s), 1.76 (3H, s), 1.43-1.29 (3H, m), 1.20-0.96 (8H, m), 0.90-0.82(6H, m).

Example 24[3-(2,4-dichloroplenyl)-4-(4-fluorophenyl)-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl}aceticacid

A solution of 2-cyclohexen-1-one (20 g, 0.208 mmol) in tetrahydrofuran(250 ml) was added to a preformed lithium diisopropylamide solution(prepared from diisopropylamine (31 ml) and n-butyllithium (140 ml, 1.6Msolution) at −70° C.) over 20 minutes and stirred for a further 20minutes. Ethyl bromoacetate (25 ml, 0.228 mmol) was added dropwise andthe reaction stirred for 1 hour warming to room temperature. Thereaction was quenched with 6N HCl (200 ml) and the product extractedinto ether (3×300 ml). Combined organic phase washed with saturatedsodium chloride, dried over magnesium sulfate and evaporated to dryness.The crude oil was purified by silica chromatography eluting withhexane-ethyl acetate mixtures (10-20%), to give ethyl(2-oxo-cyclohex-3-enyl)acetate as a colourless oil, 11.8 g. 1H NMR δ(ppm) (CDCl₃): 6.98-6.94 (1H, m), 6.03-6.00 (1H, m), 4.19-4.11 (2H, m),2.92-2.82 (2H, m), 2.49-2.41 (2H, m), 2.30-2.23 (1H, m), 2.16-2.11 (1H,m), 1.87-1.77 (1H, m) and 1.28-1.24 (3H, m).

This ester (4 g, 0.022 mmol), copper (I) bromide-dimethyl sulfidecomplex (4.88 g, 0.023 mmol) in dimethyl sulfide (20 ml) andtetrahydrofuran (120 ml) was cooled to −40° C. under nitrogen andtreated dropwise with 4-fluorophenylmagnesium bromide (1M solution inTHF, 43.9 ml) so that the temperature did not rise above −40° C.Reaction was stirred for 20 minutes before quenching with 1N HCl (300ml) and extracting the products with ether (3×300 ml). Combined organicphase washed with saturated sodium chloride, dried over magnesiumsulfate and evaporated to dryness. The crude oil was purified by silicachromatography eluting with hexane-ethyl acetate mixtures (10-20%), togive ethyl [4-(4-fluorophenyl)-2-oxo-cyclohexyl]acetate as a colourlessoil, 2.8 g. ¹H NMR δ (ppm) (CDCl₃): 7.26-7.11 (2H, m), 7.04-6.94 (2H,m), 4.18-4.11 (2H, m), 3.55-3.44 (1H, m), 3.00-2.90 (1H, m), 2.80-2.73(2H, m), 2.69-2.55 (1H, m), 2.28-2.17 (2H, m), 2.10-1.88 (2H, m),1.61-1.42 (1H, m) and 1.31-1.25 (3H, m).

The ester from the foregoing step was transformed to the desired produceusing the procedures of Example 1, steps 1-3 with the foregoing esterused in place of ethyl cyclohexanoneacetate in Step 1. Finalpurification by flash column chromatography (30% EtOAc/hexane) affordedthe title compound as a mixture of diastereomers. ¹H NMRδ (ppm)(CDCl₃):7.67-6.64 (24H, m), 5.26-5.16 (2H, m), 4.05-3.88 (2H, m), 3.51-3.43 (1H,m), 3.13-3.05 (1H, m) 2.78-2.73 (4H, m), 2.43-0.82 (28H, m).

Example 25 Example 25a((7R)-3-(2,4-dichlorophenyl)-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid andExample 25b((7S)-3-(2,4-dichlorophenyl)-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid

Step 1

To intermediate 21 (0.228 mol) was added Intermediate 19 (30 g, 0.148mmol) and propionic acid (1.65 ml, 22.2 mmol). This mixture was heatedat 125° C. for 16 h. The mixture was diluted with ethyl acetate, washedtwice with 2N HCl and once with water, then dried over sodium sulfateand evaporated to dryness. The crude oil was purified by silicachromatography eluting with (1-5% ethyl acetate/hexanes), to givedesired ethyl{3-[1-(2,4-dichlorophenyl)prop-2-en-1-yl]-2-oxocyclohexyl}acetate as acolourless oil (33 g) as a 1.75:1 mixture of diastereomers A and B. ¹HNMR δ (ppm)(CDCl₃): 7.43-7.13 (6H, m A+B), 6.09-5.99 (1H, m, A),5.82-5.72 (1H, m, B), 5.08-4.96 (4H, m, A+B), 4.47-4.33 (2H, m, A+B),4.14-3.99 (4H, m, A+B), 3.13-3.01 (2H, m, A+B), 2.87-2.73 (2H, m, A+B),2.58-2.33 (2H, m, A+B), 2.22-1.88 (6H, m, A+B), 1.77-1.35 (6H, m, A+B),1.28-1.20 (8H, m, A+B). An additional 30 g of product contaminated withethyl (2-oxocyclohexyl)acetate was obtained.

Step 2

Ethyl {3-[1-(2,4-dichlorophenyl)prop-2-en-1-yl]-2-oxocyclohexyl}acetate(3.5 g, 9.48 mmol) was dissolved in methanol (40 ml) and dichloromethane(80 ml) and cooled to −78° C. Nitrogen and then oxygen were bubbledthrough the reaction mixture for 5 mins each. Ozone was then bubbledthrough the reaction mixture until the reaction became a blue colour(1.5 hours). Nitrogen was then bubbled through the reaction for 5 minand dimethylsulfide (7 ml, 94.8 mmol) was added. The reaction wasallowed to warm to room temperature and stirred for 16 h, thenconcentrated in vacuo. After dilution with ethyl acetate, the mixturewashed twice with water, dried over sodium sulfate and concentrated invacuo. The mixture containing the desired diketone and ketals was takeninto the next step without further purification.

Step 3

Half of the mixture from the foregoing step (4.74 mmol) was dissolved intoluene (70 ml) and intermediate 8 (1.39 g, 5.69 mmol), acetic acid (0.5ml) and lithium perchlorate (504 mg, 4.74 mmol) added. A Dean-Starkapparatus was attached and the mixture refluxed for 72 h. After cooling,the reaction was quenched with sodium bicarbonate (sat. aq.) andfiltered though Celite™. The aqueous layer was extracted three timeswith ethyl acetate and the combined organic layers were dried oversodium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography to give the title compound (1.01 g), a 1:1 mixtureof diastereomers A and B, as a pale yellow oil. ¹H NMR δ (ppm)(CDCl₃):7.60-7.52 (4H, m, A+B), 7.46 (2H, d, J=2.0 Hz, A+B), 7.34-7.28 (4H, m,A+B), 7.24-7.20 (2H, m, A+B), 7.15 (2H, d, J=8.0 Hz A/B), 7.05 (1H, s,A), 6.94 (1H, s, B), 5.18-5.08 (2H, m, A+B), 4.23-4.07 (4H, m),3.41-3.34 (1H, m, B), 3.04-2.98 (1H, m, A), 2.59 (2H, d, J=8.7 Hz A+B),2.46-2.38 (4H, m, A+B), 2.27-2.19 (2H, m, A+B), 2.12-2.04 (6H, m, A+B),1.93 (1H, d, J=15.6 Hz, A/B), 1.80-1.58 (10H, m A+B), 1.43 (1H, d, J=6.6Hz, A/B), 1.34-1.20 (6H, m, A+B), 0.94-0.86 (12H, m, A+B); m/z (ES⁺) 581(MH⁺).

Step 4 Hydrolysis was performed by the method of Example 1 Step 3. Theresidue was purified by column chromatography to give((7RS)-3-(2,4-dichlorophenyl)-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid (830mg), as a 1:1 mixture of diastereomers A and B, as a colourless foam. ¹HNMR δ (ppm)(CDCl₃): 7.59 (2H, d, J=8.2 Hz B), 7.55 (2H, d, J=8.2 Hz, A),7.47 (2H, s, A+B), 7.35-7.28 (4H, m, A+B), 7.24-7.21 (2H, m, A+B), 7.13(2H, d, J=8.1 Hz), 7.05 (1H, s), 6.96 (1H, s), 5.14-5.07 (2H, m),3.40-3.36 (1H, m, B), 3.06-3.01 (1H, m, A), 2.71-2.63 (2H, m, A),2.50-2.34 (4H, m, A+B), 2.29 (1H, dd, J=11.0, 15.6 Hz, B), 2.24-2.02(5H, m, A+B), 1.88-1.53 (10H, m, A+B), 1.51-1.41 (1H, d, J=4.6 Hz, A),1.34-1.12 (3H, m, A+B), 0.93-0.83 (12H, m, A+B); m/z (ES⁺) 550 (M−H⁺).

The diastereomers could be separated by supercritical fluidchromatography (CHIRALCELOJ-H 250×10 mm (5μ) column) Column temperature40° C., Mobile phase: 85/15 CO₂/MeOH, Flow rate: 10 mL/min, outletpressure 100 bar.

Example 25a((7R)-3-(2,4-dichlorophenyl)-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid eluted at 3.56 min; ¹H NMR δ (ppm)(CDCl₃): 7.59 (2H, d, J=8.2 Hz),7.46 (1H, d, J=2.1 Hz), 7.34-7.29 (3H, m), 7.23 (1H, dd, J=8.1, 2.2 Hz),6.95 (1H, s), 5.12 (1H, t, J=7.7 Hz), 3.40-3.35 (1H, m), 2.48-2.44 (2H,m), 2.29 (1H, dd, J=11.0, 15.8 Hz), 2.14-2.08 (2H, m), 2.05-1.99 (1H,m), 1.88-1.80 (3H, m), 1.70-1.50 (2H, s), 1.25-1.15 (2H, m), 0.88-0.86(6H, m).

Example 25b((7S)-3-(2,4-dichlorophenyl)-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid eluted at 4.41 min; ¹H NMR δ (ppm)(CDCl₃): 7.55 (2H, d, J=8.1 Hz),7.46 (1H, d, J=2.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.22 (2H, dd, J=8.4, 2.1Hz), 7.13 (2H, d, J=8.1 Hz), 7.05 (1H, s), 5.09 (1H, dd, J=5.6, 9.6 Hz),3.07-3.01 (1H, m), 2.71-2.63 (2H, m), 2.45-2.42 (2H, m), 2.25-2.17 (1H,m), 2.11-2.04 (1H, m), 1.82-1.77 (2H, m), 1.73-1.66 (3H, m), 1.43-1.41(1H, m), 1.34-1.24 (1H, m), 0.93 (3H, d, J=3.3 Hz), 0.92 (3H, d, J=3.3Hz).

Example 26—(3-(2,4-Dichlorophenyl)-1-{3-phenyl-1-[4-(trifluoromethyl)phenyl]propyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid

Intermediate 3 (0.2 g, 0.54 mmol) and the product from Example 25, Step2 (0.18 g, 0.65 mmol) were dissolved in toluene (15 ml). Lithiumperchlorate (57 mg, 0.54 mmol) and acetic acid (3 μl, 0.05 mmol) wereadded and the mixture was refluxed in a Dean Stark apparatus for 2 days.It was then diluted with AcOEt (20 ml), washed with a saturated solutionof NaHCO₃ (20 ml), dried over MgSO₄ and concentrated in vacuo.Purification by chromatography on silica gel eluting with 5%AcOEt/Hexane afforded 30 mg of impure ethyl(3-(2,4-dichlorophenyl)-1-{3-phenyl-1-[4-(trifluoromethyl)phenyl]propyl}-4,5,6,7-tetrahydro-1H-indo1-7-yl)acetate that was directly used in the next step; m/z (ES⁺) 614(MH⁺).

The ester from the foregoing step (0.03 g, 0.05 mmol) was dissolved in amixture of dioxane (7 ml)/water (2 ml). Then LiOH (12 mg, 0.5 mmol) wasadded and the solution heated to 60° C. for 14 h. The reaction mixturewas then diluted with AcOEt (20 ml), washed with 2.0N HCl (20 ml), brine(20 ml), dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by chromatography on silica gel eluting with 20% AcOEt/Hexaneand consequently by HPLC (gradient 60-98% CH₃CN/0.1% TFA-H₂0) to afford1.2 mg of the title compound; m/z (ES⁺) 586 (MH⁺); m/z (ES⁻) 584 (M−H⁺).

Example 27(1-{4,4-Dimethyl-1-[4-(trifluoromethyl)phenyl]pentyl}-2-isopropyl-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Ethyl [3-(3-methyl-2-oxobutyl)-2-oxocyclohexyl]acetate (0.25 g, 0.93mmol) (prepared using the procedure of example 25 step 1 [usingintermediate 16 in place of Intermediate 19] followed by the procedureused in the preparation of intermediate 13) and intermediate 5 (0.29 g,1.1 mmol) were dissolved in toluene (25 ml). Lithium perchlorate (99 mg,0.93 mmol) and acetic acid (5 μl, 0.09 mmol) were added and the mixturewas refluxed in a Dean Stark apparatus for 12 hours. It was then dilutedwith AcOEt (20 ml), washed with a saturated solution of NaHCO₃ (20 ml),dried over MgSO₄ and concentrated in vacuo. Purification bychromatography on silica gel eluting with 5% AcOEt/Hexane afforded 40 mgof impureethyl(1-{4,4-dimethyl-1-[4-(trifluoromethyl)phenyl]pentyl}-2-isopropyl-4,5,6,7-tetrahydro-1H-indol-7-yl)acetatethat was directly used in the next step; m/z (ES⁺) 492 (MH⁺).

Impure ester from the foregoing step (40 mg, 0.08 mmol) was dissolved ina mixture of THF (5 ml)/water (1 ml) then LiOH (20 mg, 0.8 mmol) wasadded and the solution heated to 60° C. for 14 h. The reaction mixturewas then diluted with AcOEt (20 ml), washed with 2.0N HCl (20 ml), brine(20 ml), dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by chromatography on silica gel eluting with 25% AcOEt/Hexaneto afford 14 mg of the title compound as a 1:1.4 mixture ofdiasteroisomers; m/z (ES⁺) 464 (MH⁺); m/z (ES⁻) 462 (M−H⁺).

Example 28(2-Isopropyl-1-{3-phenyl-1-[4-(trifluoromethyl)phenyl]propyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared by analogy to Example 27 using intermediate 3 in place ofintermediate 5; m/z (ES⁺) 484 (MH⁺); m/z (ES⁻) 482 (M−H⁺).

Example 29(2-Isopropyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared by analogy to Example 27 using intermediate 8 in place ofintermediate 5; m/z (ES⁻) 448 (M−H⁺). Diastereomers were separated bySFC by analogy to Example 25.

Example30-2-Isopropyl-1-{(15)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-7-(1H-tetrazol-5-ylmethyl)-4,5,6,7-tetrahydro-1H-indole

The product from Example 29 (0.35 g, 0.78 mmol) was dissolved in dioxane(10 ml). NH₃ 0.5M in dioxane (1.87 ml, 0.93 mmol) was added followed byHOBT (158 mg, 1.2 mmol), EDC.HCl (224 mg, 1.2 mmol) and DIEA (0.35 ml,1.95 mmol). The mixture was stirred at RT for 14 hours. It was thendiluted with dichloromethane (30 ml), washed with water (20 ml), brine(20 ml) and concentrated under reduced pressure. Purification bychromatography on silica gel eluting with a gradient 20-25% AcOEt/Hexaneafforded the desired amide (350 mg, quantitative yield) as a colourlesssolid (m/z (ES⁺) 449 (MH⁺)) which was dissolved in dichloromethane (10ml) and Burgess reagent (0.37 g, 1.5 mmol) added. The mixture wasstirred at RT for 14 hours and after evaporation of the solvent underreduced pressure the residue was purified by chromatography on silicagel eluting with 10% AcOEt/Hexane to afford the desired nitrile (250 mg,74%) as a colourless oil (m/z (ES⁺) 431 (MH⁺)) which was dissolved inDMF (10 ml). NaN₃ (378 mg, 0.58 mmol) and NH₄Cl (310 mg, 0.58 mmol) wereadded and the mixture was heated to 125° C. for 14 hours. It was thendiluted with AcOEt (30 ml), washed with 0.1N HCl (10 ml), brine (10 ml),dried over MgSO₄ and concentrated. Purification by chromatography onsilica gel eluting with 20% AcOEt/Hexane afforded the desired tetrazoleas a 1:1 mixture of diasteroisomers (7 mg, 3%); ¹H NMR δ (ppm)(CDCl₃,360 MHz): 7.54-7.49 (4H, m, A+B), 7.26-7.22 (2H, m, A+B), 7.14-7.12 (2H,m, A+B), 5.87 (1H, s, A/B), 5.84 (1H, s, A/B), 5.38-5.36 (1H, m, A/B),5.32-5.28 (1H, m, A/B), 3.42-3.30 (2H, m, A+B), 3.21-2.92 (4H, m, A+B),2.58-2.45 (4H, m, A+B), 1.74-1.49 (6H, m, A+B), 1.46-1.33 (2H, m, A+B),1.24-1.20 (6H, m A+B), 1.15-1.09 (6H, m, A+B), 0.95-0.86 (12H, m, A+B);m/z (ES⁺) 474 (MH⁺); m/z (ES⁻) 472 (M−H⁺).

Example 31(1-{[4-(trifluoromethyl)phenyl]methyl}-2-isopropyl-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared by analogy to Example 27 using 4-(trifluoromethyl)benzylaminein place of intermediate 5; m/z (ES⁻) 378 (M−H⁺).

Example 32(1-{[4-(Trifluoromethyl)phenyl]methyl}-2-tert-butyl-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared by analogy to Example 19 using 1-bromo-3,3-dimethylhexan-2-onein place of 2-bromo-1-phenylethanone in step 1 and4-(trifluoromethyl)benzylamine in place of intermediate 1 in step 2; m/z(ES⁻) 392 (M−H⁺).

Example 33 2-Isopropyl-1-{(1S)-4-methyl1-[4-(trifluoromethyl)phenyl]pentyl}-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-6-yl)aceticacid

Ethyl (2-pyrrolidin-1-ylcyclopent-2-en-1-yl)acetate was prepared from2-cyclopentanone acetate using the procedure used to prepareintermediate 2 and was alkylated with prenyl bromide using the procedureof example 19, step 1 to afford ethyl[3-(3-methylbut-2-en-1-yl)-2-oxocyclopentyl]acetate as a mixture ofdiastereomers; ¹H NMR δ (ppm)(CDCl₃): 5.10-5.04 (1H, m), 4.17-4.07 (2H,m), 2.84-2.51 (2H, m), 2.48-2.14 (4H, m), 2.12-2.06 (1H, m), 2.02-1.88(1H, m), 1.73-1.61 (7H, m), 1.55-1.45 (1H, m), 1.28-1.22 (3H, m).

This mixture (4.0 g, 15.87 mmol) was dissolved in dichloromethane (50ml) and cooled to 0° C. m-CPBA (70%, 4.28 g, 17.46 mmol) was addedcarefully, and the mixture then stirred for 1 h. The reaction wasquenched with 1N NaOH and extracted three times with ethyl acetate andthen the combined organics washed with 1N NaOH and brine. The organicswere dried over sodium sulfate, concentrated and the crude ethyl{3-[(3,3-dimethyloxiran-2-yl)methyl]-2-oxocyclopentyl}acetate purified(20% ethyl acetate/hexanes) by a very quick silica plug column and useddirectly in the next reaction.

The foregoing product (4.28 g, 15.87 mmol) was dissolved in toluene (70ml) and lithium perchlorate added (1.68 g, 15.87 mmol). The reaction washeated to reflux and stirred for 2 h. After cooling, the reaction wasquenched with saturated aqueous sodium bicarbonate, extracted threetimes with ethyl acetate, dried over sodium sulfate and concentrated.The crude product was purified by column chromatography (5-10% ethylacetate/hexanes) to afford the desired ethyl[3-(3-methyl-2-oxobutyl)-2-oxocyclopentyl]acetate (3.6 g) as acolourless oil; ¹H NMR δ (ppm)(CDCl₃): 4.16-4.10 (2H, m), 3.08-2.82 (2H,m), 2.77-2.71 (1H, m), 2.69-2.59 (1H, m), 2.55-2.37 (1H, m), 2.25-2.07(2H, m), 2.01-1.71 (2H, m), 1.43-1.31 (1H, m), 1.28-1.22 (2H, m), 1.19(2H, d, J 9.6 Hz), 1.13-1.09 (6H, m).

This ethyl [3-(3-methyl-2-oxobutyl)-2-oxocyclopentyl]acetate wastransformed to the desired2-isopropyl-1-{(18)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-6-yl)aceticacid using the procedures from Example 25, steps 3 and 4; m/z (ES⁻) 434(M−H⁺).

Example 34(2-[4-(trifluoromethyl)phenyl]-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using the procedures from Example 25, steps 1-4. In step 1,intermediate 18 was used in the place of Intermediate 19; m/z (ES⁻) 550(M-H⁺). Diastereomers were separated by SFC by analogy to Example 25.

Example 35(2-Methyl-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using procedures from Example 22 using intermediate 10 in placeof intermediate 1 in step 2; m/z (ES⁻) 392 (M-H⁺).

Example 36(2-Isopropyl-1-{(1R)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using the procedure of example 25 step 1-4 using intermediate16 in place of Intermediate 19 in step 1, and the procedure used in thepreparation of intermediate 13 instead of example 25 step 2. In step 3,ent-intermediate 8 was used in place of intermediate 8; m/z (ES⁻) 448(M−H⁺). Diastereomers were separated by SFC by analogy to Example 25.

Example 37(2-Isopropyl-1-{(is)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using the procedure of example 25 step 1-4 using intermediate16 in place of Intermediate 19 in step 1, and the procedure used in thepreparation of intermediate 13 instead of example 25 step 2. In step 3,intermediate 9 was used in place of intermediate 8; m/z (ES⁻) 420(M−H⁺). Diastereomers were separated by SFC by analogy to Example 25.

Example 38 (6-ethyl-2-isopropyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid

Prepared using the procedures from Example 25, steps 1-4 usingintermediate 16 in place of Intermediate 19 in step 1, and the procedureused in the preparation of intermediate 13 instead of example 25 step 2.Also in step 1, a mixture of ethyl[(1R,6S)-2-ethoxy-6-ethylcyclohex-2-en-1-yl]acetate and ethyl[(1R,6S)-2,2-diethoxy-6-ethylcyclohexyl]acetate [prepared fromintermediate 14 and the procedure used for the preparation ofintermediate 21], was used in place of intermediate 21; m/z (ES⁻) 476(M−H⁺). Diastereomers were separated by SFC by analogy to Example 25.

Example 39(2-Isopropyl-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using the procedure of example 25 step 1-4 using intermediate16 in place of Intermediate 19 in step 1, and the procedure used in thepreparation of intermediate 13 instead of example 25 step 2. In step 3,intermediate 10 was used in place of intermediate 8; m/z (ES⁻) 420(M−H⁺).

Example 40(2-Cyclohexyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using the procedures from Example 25, steps 1-4 (usingintermediate 17 in the place of Intermediate 19 in step 1); m/z (ES⁻)488 (M−H⁺). Diastereomers were separated by SFC by analogy to Example25.

Example 41(2-Isopropyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using the procedures from Example 25, steps 1 and 2 (usingintermediate 20 in the place of Intermediate 19 in step 1) followed bythe procedure from example 21, step 2 and finally the procedure fromexample 1, step 3; m/z (ES⁻) 558 (M−H⁺). Diastereomers were separated bymass directed HPLC (Agilent System) by analogy to Example 25.

Example 42(2-Isopropyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using the procedures from Example 25, steps 1-4.(2E)-3-(2,4-dichlorophenyl)-2-isopropylprop-2-en-1-ol [prepared byanalogy to intermediate 20] was used in the place of Intermediate 19 instep 1) and 4-(trifluoromethyl)benzylamine was used in the place ofintermediate 8 in step 3; m/z (ES⁻) 522 (M−H⁺).

Example 43(3-(2,4-dichlorophenyl)-1-{(1R)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic

Prepared using the procedures from Example 25, steps 1-4 usingent-intermediate 8 in place of intermediate 8 in step 3; m/z (ES⁻) 550(M−H⁺). Diastereomers were separated by SFC by analogy to Example 25.

Example 44 (3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetra hydro-1H-indol-7-yl)acetic acid

Prepared using the procedures from Example 25, steps 1-4 usingintermediate 11 in place of intermediate 8 in step 3; m/z (ES⁻) 536(M−H⁺). Diastereomers were separated by SFC by analogy to Example 25.

Example45-3-phenyl-1-{(1S)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid

Prepared using the procedures from Example 25, steps 1-4 using cinnamylalcohol in the place of Intermediate 19 in step 1; m/z (ES⁻) 482 (M−H⁺).Diastereomers were separated by SFC by analogy to Example 25.

Example46-{3-(2,4-dichlorophenyl)-1-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydro-1H-indol-7-yl}aceticacid

Prepared using the procedures from Example 25, steps 1-4 using4-(trifluoromethyl)benzylamine in place of intermediate 8 in step 3; m/z(ES⁻) 480 (M−H⁺).

Example47-{3-(2-methyl-2-propyl)-1-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydro-1H-indol-7-yl}aceticacid

Prepared using the procedures from Example 25, steps 1-4 usingintermediate 15 in place of Intermediate 19 in step 1 and4-(trifluoromethyl)benzylamine in place of intermediate 8 in step 3; m/z(ES⁻) 392 (M-H⁺).

Example 48(3-(2-methyl-2-propyl)-1-{(1R)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared using the procedures from Example 25, steps 1 and 2 (usingintermediate 15 in place of Intermediate 19 in step 1) followed by theprocedure from example 21, step 2 (using ent-intermediate 8 in place ofintermediate 8) and finally the procedure from example 1, step 3; m/z(ES⁻) 462 (M−H⁺). Diastereomers were separated by SFC by analogy toExample 25.

Examples 49-66

Examples 49-66 were prepared following the procedures of Examples 1 or2. In step 1, intermediate 9, 10, 22 or ent-intermediate 8 was used asappropriate. In step 2, the appropriate nitroalkene was used:—when notavailable commercially, the nitroalkenes were prepared by publishedmethods, e.g. base-catalysed condensation of R¹CHO with nitromethane.The products were generally isolated as a mixture of two diastereomerswhich could be separated using SFC or mass-directed HPLC methodsanalogously to those described previously. m/z (ES⁻) Ex. No. R₁ R₂ R₃ (M− H⁺) 49 2-nitrophenyl H n-propyl 499 50 4-tert-butylphenyl H n-propyl510 51 2,5-dimethylphenyl H n-propyl 482 52 4-chloro-2- H 4-methylbutyl534 fluorophenyl 53 2,4-bis(CF₃)phenyl H n-propyl 590 54 4-cyanophenyl Hn-propyl 481 55 2,5-bis(CF₃)phenyl n-propyl H 590 56 2,4-difluorophenylH 4-methylbutyl 518 57 2,4,6-trichlorophenyl H n-propyl 556 582,5-bis(CF₃)phenyl H 4-methylbutyl 618 59 4-(CF₃O)phenyl H n-propyl 53860 2,5-dichlorophenyl H 4-methylbutyl 550 61 4-(CF₃)phenyl H n-propyl522 62 2,4-dimethylphenyl H n-propyl 482 63 2,4-dichlorophenyl H3-methylpropyl 536 64 2,4-dimethoxyphenyl H n-propyl 514 652,5-bis(CF₃)phenyl H n-propyl 590 66 4-methylnaphth-1-yl H n-propyl 520

Example67-(3-[2-methyl-4-chlorophenyl]-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared by analogy to example 17 using methylboronic acid in place ofn-butylboronic acid; m/z (ES⁻) 502 (M−H⁺).

Example 68(3-[2-phenyl-4-chlorophenyl]-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared by analogy to example 17 using phenylboronic acid in place ofn-butylboronic acid; m/z (ES⁻) 564 (M−H⁺).

Example 69(3-(2,4-dichlorophenyl)-1-{1-[4-(trifluoromethyl)phenyl]butyl}-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-6-yl)aceticacid

Prepared following the procedures of Example 2. In step 1,2-cyclopentanone acetate was used in place of cyclohexanone acetate. m/z(ES⁻) 508 (M−H⁺).

Example 70 (3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrol-8-yl)aceticacid

Prepared following the procedures of Example 2. In step 1,2-cycloheptanone acetate was used in place of cyclohexanone acetate andintermediate 10 was used in place of intermediate 1. m/z (ES⁻) 536(M−H⁺).

Example 71(3-(2,4-Dichlorophenyl)-1-{1-[2,5-bis(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared following the procedures of Example 2. In step 1, intermediate7 was used in place of intermediate 1. m/z (ES⁻) 590 (M−H⁺).

Example 72(3-(2,4-Dichlorophenyl)-1-{1-[2,4-bis(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared following the procedures of Example 2. In step 1, intermediate6 was used in place of intermediate 1. m/z (ES⁻) 590 (M−H⁺).

Example 73 ((6S)-3-(2,4-dichlorophenyl)-6-ethyl1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared following the procedures of Example 2. In step 1, intermediate14 was used in place of 2-cyclohexanone acetate and intermediate 10 wasused in place of intermediate 1. m/z (ES⁻) 550 (M−H⁺).

Example 74((6S)-3-(4-chlorophenyl)-6-ethyl-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared following the procedures of Example 2. In step 1, intermediate14 was used in place of 2-cyclohexanone acetate and intermediate 10 wasused in place of intermediate 1. In step2,2-(4-chlorophenyl)-1-nitroethene was used in place of2-(2,4-dichlorophenyl)-1-nitroethene. m/z (ES⁻) 516 (M−H⁺).

Example 75((6S)-3-(2,4-dichlorophenyl)-6-ethyl-1-{(1R)-4-methyl-1-[4-(trifluoromethyl)phenyl]pentyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)aceticacid

Prepared following the procedures of Example 2. In step 1, intermediate14 was used in place of 2-cyclohexanone acetate and ent-intermediate 8was used in place of intermediate 1. m/z (ES⁻) 578 (M−H⁺).

Example 76(3-(2,4-dichlorophenyl)-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indazol-7-yl)aceticacid

Intermediate 2 (2 g, 8.44 mmol) was dissolved in dioxane (50 ml) andtriethylamine (1.18 ml, 8.44 mmol) and 2,4-dichlorobenzoyl chloride(1.76 g, 844 mmol) added. The reaction mixture was stirred at reflux for16 h. The mixture was then allowed to cool and diluted with ethylacetate and washed with saturated sodium bicarbonate and then brine. Theorganics were dried over sodium sulfate and purified by columnchromatography to give the desired ethyl[3-(2,4-dichlorobenzoyl)-2-oxocyclohexyl]acetate (220 mg) as acolourless oil. ¹H NMR δ (ppm)(CDCl₃): 7.36 (1H, d, J=2.0 Hz), 7.23,(1H, dd, J=8.3, 2.0 Hz), 7.12 (1H, d, J=8.3 Hz), 4.13-4.07 (2H, m),2.93-2.84 (1H, m), 2.78 (1H, dd, J=16.1, 5.9 Hz), 2.45 (1H, dd, J=16.1,8.3 Hz), 2.11-1.84 (4H, m), 1.70-1.62 (1H, m), 1.51-1.40 (2H, m), 1.20(3H, t, J=7.0 Hz).

The diketone from the foregoing step (50 mg, 0.14 mmol) and the HCl saltof intermediate 23 (200 mg) were dissolved in NMP and heated in a Smithmicrowave reactor for 50 min at 220° C. The mixture was then dilutedwith ethyl acetate and water. The layers were separated and the aqueouslayer was extracted with further ethyl acetate. The combined organicswere dried (sodium sulfate) and concentrated and then taken back up indiethyl ether. 1N HCl in ether was added and the reaction mixturefiltered. The filtrate was concentrated and taken up in DMSO andpurified by mass directed HPLC to afford the desired pyrazole; m/z (ES⁺)553 (M+H⁺) which was hydrolysed using the procedure of Example 1 Step 3to give the desired product; m/z (ES⁻) 523 (M−H⁺).

1. A compound of formula I:

wherein V represents a bond, CH₂ or CH₂CH₂; X represents CR^(1a) or N; Yrepresents CO₂H or tetrazole; Ar represents phenyl which optionallybears up to 3 substituents independently selected from hydrocarbongroups of up to 6 carbon atoms and (CH₂)_(m)-Z where m is 0, 1 or 2 andZ represents halogen, N₃, CN, CF₃, OCF₃, OR⁴, S(O)_(t)R⁴ where t is 0, 1or 2, CO₂R⁴, tetrazole, N(R⁴)₂, NHCOR⁵, NHCON(R⁴)₂, CON(R⁴)₂, SO₂N(R⁴)₂,NHSO₂R⁵, COR⁵, or OCOR⁵; R¹ represents H or a nonaromatic hydrocarbongroup of up to 10 carbon atoms optionally substituted with up to 3halogen substituents or with CN, CF₃, OR⁴, S(O)_(t)R⁴ where t is 0, 1 or2, CO₂R⁴, CON(R⁴)₂, SO₂N(R⁴)₂, COR⁴, OCOR⁵ or NR⁴COR⁵; or R¹ representsphenyl, naphthyl, benzyl or heteroaryl any of which optionally bears upto 3 substituents selected from halogen, CF₃, OCF₃, CN, NO₂R⁵, OR⁴,CO₂R⁴, S(O)_(t)R⁴ where t is 0, 1 or 2, CON(R⁴)₂, SO₂N(R⁴)₂, COR⁴, OCOR⁵or NR⁴COR⁵; R^(1a) has the same definition as R¹; each R² isindependently H or C₁₋₄alkyl; R³ is H or a hydrocarbon group containingup to 10 carbon atoms which is optionally substituted with halogen, CF₃,C₁₋₄alkoxy or C₁₋₄alkylthio; R⁴ represents H or a hydrocarbon group ofup to 7 carbon atoms, optionally substituted with halogen, CN, CF₃, OH,C₁₋₄alkoxy or C₁₋₄alkoxycarbonyl; or two R⁴ groups attached to the samenitrogen atom may complete a 5- or 6-membered heterocyclic ring; R⁵represents R⁴ that is other than H; p is 0, 1 or 2; and R⁶ representsC₁₋₆alkyl, C₂₋₆alkenyl or phenyl, benzyl or heteroaryl, said phenyl,benzyl or heteroaryl optionally bearing up to 3 substituents selectedfrom halogen, CN, CF₃, OCF₃, OR⁴, CO₂R⁴, COR⁴, OCOR⁵ and C₁₋₄alkyl; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 of formula II:

or a pharmaceutically acceptable salt thereof, wherein V, Ar, p, R¹,R^(1a), R2, R³ and R⁶ are as defined in claim
 1. 3. A compound accordingto claim 1 of formula III:

or a pharmaceutically acceptable salt thereof; wherein V, Ar, p, R^(1a),R², R³ and R⁶ are as defined in claim
 1. 4. A compound according toclaim 2 wherein R¹ is selected from H, hydrocarbon atoms and phenylwhich optionally bears up to 3 substituents selected from halogen,C₁₋₆alkyl, OCF₃, methoxy and CF₃.
 5. A compound according to claim 3wherein R^(1a) is selected from C₁₋₆alkyl, C₃₋₇cycloalkyl and phenylwhich optionally bears up to 3 substituents selected from halogen,C₁₋₆alkyl, OCF₃, methoxy and CF₃.
 6. A compound according to claim 1 inwhich V represents CH₂ and each R² is H.
 7. A compound according toclaim 1 in which R³ is an alkyl group of 2 to 6 carbon atoms.
 8. Acompound according to claim 1 in which Ar is 4-trifluoromethylphenyl. 9.A pharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier. 10.-11. (canceled)
 12. Amethod of treating or preventing a disease associated with deposition ofAβ in the brain comprising administering to a patient in need thereof atherapeutically effective amount of a compound according to claim
 1. 13.A process for preparing a compound of formula I as defined in claim 1 inwhich X represents CR^(1a), comprising reaction of an amine of formula:

with a 1,4-dicarbonyl compound of formula:

followed by hydrolysis, wherein R represents methyl or ethyl and allother variables are as defined in claim 1.